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RNA. Sep 2010; 16(9): 1725–1747.
PMCID: PMC2924533

Of proteins and RNA: The RNase P/MRP family


Nuclear ribonuclease (RNase) P is a ubiquitous essential ribonucleoprotein complex, one of only two known RNA-based enzymes found in all three domains of life. The RNA component is the catalytic moiety of RNases P across all phylogenetic domains; it contains a well-conserved core, whereas peripheral structural elements are diverse. RNA components of eukaryotic RNases P tend to be less complex than their bacterial counterparts, a simplification that is accompanied by a dramatic reduction of their catalytic ability in the absence of protein. The size and complexity of the protein moieties increase dramatically from bacterial to archaeal to eukaryotic enzymes, apparently reflecting the delegation of some structural functions from RNA to proteins and, perhaps, in response to the increased complexity of the cellular environment in the more evolutionarily advanced organisms; the reasons for the increased dependence on proteins are not clear. We review current information on RNase P and the closely related universal eukaryotic enzyme RNase MRP, focusing on their functions and structural organization.

Keywords: ribonuclease P, RNase P, ribonuclease MRP, RNase MRP, ribozyme, ribonucleoprotein


Ribonuclease (RNase) P holds a special place among RNA-based catalytic molecules. The endonucleolytic cleavage of pre-tRNA by the RNA component of bacterial RNase P was one of the first examples of RNA-catalyzed reactions (Guerrier-Takada et al. 1983). RNase P is a naturally occurring multiturnover RNA-based enzyme found in all three domains of life (Altman and Kirsebom 1999). The homology of the RNA components of RNase P throughout the three domains of life strongly suggests that it is an ancient enzyme that was present in the last universal common ancestor and, possibly, is a remnant of the prebiotic RNA world (Gilbert 1986; Altman and Kirsebom 1999; Hartmann and Hartmann 2003; Gesteland et al. 2006; Sun and Caetano-Anolles 2010, and references therein). For reasons that are not clear, and despite the general domination of protein-based catalysis, RNase P remains a universally RNA-based enzyme (with currently known exceptions being some endosymbiont organelles, wherein the RNA-based RNase P is replaced by protein-based enzymes) (Gegenheimer 1996; Thomas et al. 2000a; Holzmann et al. 2008; Gobert et al. 2010; for review, see Walker and Engelke 2006, 2008; Lai et al. 2010).

The RNA component is the catalytic moiety in the RNA-based RNases P from all domains of life (Guerrier-Takada et al. 1983; Pannucci et al. 1999; Thomas et al. 2000b; Kikovska et al. 2007; Li et al. 2009). However, as discussed in this review, RNase P holoenzymes are ribonucleoproteins with protein moieties that significantly affect their activities and are universally required in vivo. In the course of evolution, the importance and the complexity of the protein moiety in RNase P grew substantially, apparently responding to the increasing complexity of the cellular environment and reflecting the delegation of some roles from the RNA to the proteins in the more evolutionarily advanced RNases P. Thus, in addition to being a fascinating case of a universally essential RNA-based enzyme, RNase P and the closely related RNase MRP may serve as a model to help us understand driving forces behind the transition from the prebiotic RNA world to modern life.


RNase P is a metalloenzyme

RNase P is a site-specific endoribonuclease. Cleavage by RNase P generates products with 5′-monophosphates and 3′-hydroxyls, similar to cleavage by Group I and Group II self-splicing introns and distinct from cleavage by small ribozymes and RNase A (for review, see Doudna and Cech 2002; Doudna and Lorsch 2005).

RNase P is a metalloenzyme, and Mg2+ or other divalent ions are crucial for its catalytic mechanism; the current understanding of the mechanism of the catalytic action of RNase P has recently been reviewed (Kirsebom and Trobro 2009). Divalent ions are also required for the correct folding of the RNA component in bacterial RNase P (Baird et al. 2007, 2010; Qu et al. 2008; Kazantsev et al. 2009; Hsieh et al. 2010, and references therein) and likely in eukaryotic RNases P as well (the removal of Mg2+ results in some changes in footprinting patterns for Saccharomyces cerevisiae RNase P holoenzyme) (O Esakova and AS Krasilnikov, unpubl.). The involvement of divalent ions in substrate binding was also reported, although divalent ions were not absolutely required for substrate binding (Smith et al. 1992; Beebe et al. 1996).

pre-tRNA is a substrate for RNase P

The universal and the best-characterized function of RNase P is the processing of the 5′-end of the precursor tRNA (pre-tRNA). With a few known exceptions (tRNAs that carry a 5′-terminal triphosphate in their mature form) (Gupta 1984; Lee et al. 1987), cleavage by RNase P is required for the maturation of the 5′-end of tRNA (Fig. 1A).

Examples of RNase P and RNase MRP substrates; cleavage sites are shown by arrows. (A) E. coli pre-tRNATyr (RNase P substrate). (B) E. coli 4.5S rRNA precursor (RNase P substrate). (C) The A3 site of S. cerevisiae pre-rRNA (RNase MRP substrate; putative ...

The recognition of pre-tRNAs by RNase P involves conserved features of the substrate. In general, the recognition by RNase P does not rely solely on an individual feature of the substrate, but rather on multiple dispersed recognizable elements that act in a cooperative manner (Kirsebom 2007; Lai et al. 2010, and references therein).

pre-tRNA recognition by bacterial RNase P

The regions of precursor tRNA recognized by bacterial RNase P include the TΨC stem–loop, D-loop, and the acceptor stem (McClain et al. 1987; Green and Vold 1988; Kahle et al. 1990; Thurlow et al. 1991; Pan et al. 1995; Loria and Pan 1997, 1998; Chen et al. 1998); the 5′-leader also plays a role in substrate recognition and substrate/product discrimination (Brannvall et al. 1998; Crary et al. 1998; Loria and Pan 1998; Niranjanakumari et al. 1998; Zahler et al. 2003, 2005; Rueda et al. 2005; Pettersson and Kirsebom 2008; Cuzic-Feltens et al. 2009). In addition, bacterial RNase P typically interacts with the 3′-end RCCA sequence found in most bacterial pre-tRNA transcripts (Sprinzl and Vassilenko 2005), and the disruption of this interaction has a negative effect on the substrate cleavage in vitro, although it does not abolish it (Guerrier-Takada et al. 1984; McClain et al. 1987; Kirsebom and Svard 1994; LaGrandeur et al. 1994; Oh and Pace 1994; Svard et al. 1996; Oh et al. 1998; Heide et al. 1999; Busch et al. 2000; Wegscheid and Hartmann 2006). The disruption of the interaction with 3′-RCCA in vivo can be detrimental (in Bacillus subtilis) (Wegscheid and Hartmann 2007) or even lethal (in Escherichia coli) (Wegscheid and Hartmann 2006). It should be noted that in some bacteria, the CCA sequence may not be present in the pre-tRNA transcripts (Sprinzl and Vassilenko 2005) and is added post-transcriptionally. In these cases the 3′-terminal CCA may not participate in substrate recognition; moreover, its presence can be detrimental for RNase P cleavage (Pascual and Vioque 1999).

Bacterial RNase P RNA is capable of cleaving minimized substrates that mimic the acceptor stem of pre-tRNA; the smallest known substrate cleaved by E. coli RNase P RNA in vitro comprises only 4 base pairs (bp) connected by a tetraloop with a single-stranded CCAC sequence at the 3′-end and a short 5′ overhang (Brannvall et al. 2007).

pre-tRNA recognition by eukaryotic RNase P

Recognition of pre-tRNA by eukaryotic RNase P requires more substrate elements than in bacteria (Yuan et al. 1992; Levinger et al. 1995; Yuan and Altman 1995; Ziehler et al. 2000). Human, Xenopus laevis, and Drosophila melanogaster RNase P can cleave minimized substrates made up of a 7-bp-long stem with a 5′ overhang, mimicking the acceptor stem in eukaryotic pre-tRNA, connected via a single-stranded linker to a second stem, which mimics the T-stem (Carrara et al. 1995; Levinger et al. 1995; Yuan and Altman 1995). In addition, interactions between eukaryotic RNase P and substrate pre-tRNA in vivo appear to be influenced by La (or, in yeast, La-like) (Yoo and Wolin 1997) proteins bound to pre-tRNA. La proteins bind nascent pre-tRNAs (as well as other RNA polymerase III transcripts) at their poly(U) 3′ termini and protect them from exonucleolytic digestion (Maraia and Intine 2001; Wolin and Cedervall 2002, and references therein). In human cells, it was shown that the La protein attenuates the processing of the 5′-ends of pre-tRNA, but this effect is alleviated by the phosphorylation of the La protein, even though the protein remains bound to the pre-tRNA (Fan et al. 1998; Intine et al. 2000). The phosphorylated La protein is proposed to facilitate pre-tRNA processing by RNase P by denaturing the secondary structure involving 3′-trailing sequences in the substrate (Xiao et al. 2002). For more details on RNase P-substrate interactions, see Kirsebom (2007), and references therein.

Additional substrates for RNase P

In addition to the ubiquitous processing of pre-tRNA, bacterial RNase P is involved in the cleavage of a variety of other naturally occurring substrates. These substrates do not necessarily closely resemble pre-tRNA and include the precursors to 4.5S RNA (Fig. 1B; Bothwell et al. 1976; Guerrier-Takada and Altman 1984b; Peck-Miller and Altman 1991), tmRNA (Komine et al. 1994), operon mRNAs (Alifano et al. 1994; Li and Altman 2003, 2004), some phage RNAs (Forti et al. 1995; Hartmann et al. 1995), OLE RNA from extremophilic bacteria (Ko and Altman 2007), and some transient structures in riboswitches (Altman et al. 2005; Seif and Altman 2008).

In S. cerevisiae, hidden-in-reading-frame antisense-1 RNA (HRA1) was identified as a potential RNase P substrate and verified as an RNase P substrate in vitro (Samanta et al. 2006; Yang and Altman 2007). Recently, the role of yeast RNase P in the splicing-independent maturation of intron-encoded box C/D small nucleolar RNAs was suggested (Coughlin et al. 2008). These snoRNAs copurified with RNase P, and their precursors accumulated in RNase P temperature-sensitive mutants. However, the cleavage sites could not be determined in in vitro reactions, possibly due to the absence of additional components bound to the substrates or their incorrect folding in vitro (Coughlin et al. 2008).

In humans, RNase P was shown to participate in the processing of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a noncoding RNA that is misregulated in many human cancers. RNase P cleaves off a tRNA-like segment in the 3′-end region of the nascent MALAT1 transcript, generating the mature 3′-end of a long MALAT1 RNA and the 5′-end of a 61-nucleotide (nt) mascRNA that resembles tRNA (Wilusz et al. 2008).

The relative simplicity of minimized RNase P substrates allows for the use of RNase P as a vehicle to down-regulate the expression of targeted genes at the mRNA level (Forster and Altman 1990; Lundblad et al. 2008; Shen et al. 2009; Lundblad and Altman 2010, and references therein). In this approach, external guide sequence (EGS) oligoribonucleotides (or their modified analogs) are introduced into cells. The EGS base pairs with the target mRNA, forming a structure that mimics the natural pre-tRNA substrate, leading to cleavage of the mRNA by RNase P. This approach has been applied for both bacterial and mammalian cells.

Eukaryotic RNase P in transcription

Perhaps the most intriguing and rather unexpected noncanonical function of RNase P is its suggested role in transcription by RNA polymerases I and III in human cells. RNase P activity was shown (Reiner et al. 2006) to coimmunoprecipitate with components of Pol III; depletion of RNase P resulted in significant reduction of the level of transcription of tRNATyr, tRNAMet, 5S rRNA, 7SL RNA, and U6 snRNA in HeLa cell extracts, and this effect was reversed by the addition of RNase P. Moreover, the knockdown of protein components of RNase P practically abolished Pol III transcription of 5S rRNA in whole HeLa cells. In addition, chromatin immunoprecipitation indicated that all analyzed protein components of RNase P associated with chromatin of actively transcribed, but not inactive, tRNA and 5S rRNA genes (Reiner et al. 2006; Jarrous and Reiner 2007). A very similar effect of the presence of RNase P was recently reported for rRNA transcription by RNA polymerase I (Reiner et al. 2008). The physical association of RNase P with the transcription machinery may set the stage for cotranscriptional processing of RNase P substrates.

The apparent versatility of substrate recognition by RNase P, the growing number of already identified substrates, and the recently reported role of RNase P in the regulation of transcription make it reasonable to expect that additional roles for RNase P are yet to be identified, both in bacteria and in eukaryotes.


RNase MRP is an essential eukaryotic endoribonuclease

In eukaryotes, the RNase P lineage has split into two, giving rise to another RNA-based site-specific endonuclease, RNase MRP (mitochondrial RNA processing) (Chang and Clayton 1987a,b; Karwan et al. 1991). Similar to RNase P, RNase MRP is essential for the viability of eukaryotic cells (Schmitt and Clayton 1992). Despite its name, the vast majority of RNase MRP is localized in the nucleolus (Chang and Clayton 1987a; Reimer et al. 1988; Yuan et al. 1989; Topper and Clayton 1990; Kiss and Filipowicz 1992) and, transiently, in the cytoplasm (Gill et al. 2006). Mitochondrial RNase MRP was suggested to be involved in processing mitochondrial RNAs, generating RNA primers for mitochondrial DNA replication (Chang and Clayton 1987a; Stohl and Clayton 1992; Topper et al. 1992). Mitochondrial RNase MRP has distinct protein moiety and specificity (Lu et al. 2010) that have not yet been fully characterized; mitochondrial RNase MRP will not be further discussed in this review.

RNase MRP is similar to eukaryotic RNase P

The RNA component of RNase MRP contains highly conserved elements that closely resemble RNase P (Figs. 2, ,3),3), and most of the protein components of RNase MRP and eukaryotic RNase P are shared (Table 1; see the detailed discussion in the eukaryotic RNases P/MRP section). Even though the catalytic ability of the RNA component of RNase MRP has not yet been demonstrated, the close similarity of one of its domains (Fig. 3C,D, Domain 1) to the conserved catalytic domain of RNase P RNA (Fig. 3A,B) and very similar protein compositions of RNase MRP and eukaryotic RNase P make it highly likely that the RNA component of RNase MRP is its catalytic moiety.

Protein components of archaeal and eukaryotic RNases P/MRP
Secondary structure diagrams for bacterial and archaeal RNase P RNAs. (A) Bacterial A-type represented by RNase P from E. coli. (B) Bacterial B-type, B. subtilis. (C) Minimized bacterial RNase P RNA (Siegel et al. 1996). (D) Archaeal A-type, P. horikoshii ...
Secondary structure diagrams for eukaryotic RNase P and RNase MRP RNAs. (A) S. cerevisiae RNase P. (B) Human RNase P. (C) S. cerevisiae RNase MRP. (D) Human RNase MRP. The conserved 5′-GARAR-3′ sequence element is underlined (C,D). Dotted ...

RNases MRP and P are physically separate complexes, which purify individually even when very mild purification techniques are used (Chamberlain et al. 1998; Jarrous et al. 1998; Srisawat and Engelke 2001). Interestingly, the total amounts of RNase MRP and RNase P in yeast appear to be approximately equal: copurification of RNases P and MRP using a tandem affinity purification (TAP) tag (Rigaut et al. 1999) attached to a common RNase P/MRP protein component Pop4 results in an ~1:1 ratio of the two RNA components (Esakova et al. 2008; ME Schmitt, pers. comm.).

RNase MRP appears to be a universal eukaryotic enzyme as it is found in practically all eukaryotes analyzed (Piccinelli et al. 2005; Rosenblad et al. 2006). The similarity of RNase MRP to the eukaryotic RNase P, its conservation throughout Eukarya, and the fact that in some protists RNase P and RNase MRP RNA genes appear in tandem (Piccinelli et al. 2005) strongly suggest a close evolutionary relationship between RNase P and RNase MRP that dates back to the early evolution of eukaryotes (Piccinelli et al. 2005; Rosenblad et al. 2006; Zhu et al. 2006; Woodhams et al. 2007).

RNase MRP in the processing of pre-rRNA

The first identified function of RNase MRP outside the mitochondria was its participation in the maturation of nuclear rRNA in yeast. Eukaryotic rRNAs (except for 5S rRNA) are transcribed by RNA polymerase I as a single precursor molecule that has to be subjected to multiple endonucleolytic cleavages and exonucleolytic trimmings to form mature rRNAs; many details of this process are still not clear (Lindahl et al. 2009, and references therein). In S. cerevisiae, RNase MRP is shown to cleave the internal transcribed spacer 1 (ITS1) at the specific site A3 of the rRNA precursor (Fig. 1C), leading, after additional trimming, to the formation of the mature 5′-end of 5.8S rRNA (Schmitt and Clayton 1993; Chu et al. 1994; Clayton 1994; Lygerou et al. 1994, 1996a). There are two forms of mature yeast 5.8S rRNA (Rubin 1974), short (5.8SS) and long (5.8SL), that differ by the presence of additional 7 nt at the 5′-end. The short form normally accounts for ~80%–90% of the total 5.8S rRNA in yeast; the biological significance of the existence of the two forms of 5.8S rRNA is not currently clear, although the presence of the two forms of 5.8S rRNA appears to be common in eukaryotes (Bowman et al. 1983; Smith et al. 1984; Henry et al. 1994). Depletion of RNase MRP or deletion of the A3 site results in the accumulation of the longer 5.8SL rRNA, while the amount of the normally more abundant short 5.8SS rRNA is greatly reduced, indicating the existence of two alternative pathways for the generation of the 5′-end of 5.8S rRNA: the major one that depends on RNase MRP cleavage at the A3 site and results in the production of 5.8SS rRNA, and the other that does not rely on the cleavage of the A3 site and results in the production of 5.8SL rRNA (Schmitt and Clayton 1993; Henry et al. 1994). Recent data obtained using several temperature-sensitive RNase MRP mutants (Lindahl et al. 2009) show that inactivation of RNase MRP results in a severe reduction of the abundance of all early intermediates in the canonical rRNA processing pathway, while the transcription of the rRNA precursor is not affected, suggesting that RNase MRP plays a key role in the processing of rRNA beyond the cleavage of the A3 site in ITS1.

RNase MRP in the regulation of the cell cycle

In addition to its role in the maturation of rRNA, RNase MRP was shown to play a role in the regulation of the cell cycle in yeast. RNase MRP mutations in S. cerevisiae led to missegregation of plasmids (Cai et al. 1999) and caused cell cycle delay at the end of mitosis, accompanied by a buildup of cyclin B2 (CLB2) protein, resulting from an increase in the concentration of CLB2 mRNA (Cai et al. 2002). RNase MRP was demonstrated to specifically cleave the 5′-UTR of CLB2 mRNA that allowed its rapid 5′-to-3′ degradation by exoribonuclease Xrn1 (Gill et al. 2004). Consistent with its role in the degradation of CLB2 mRNA, after the initiation of mitosis and until the completion of telophase, a fraction of the total RNase MRP was shown to accumulate in a discrete cytoplasmic spot, where it might be involved in the degradation of CLB2 mRNA (Gill et al. 2006).

Considering the degree of RNase MRP involvement in the processing of rRNA, which is still not well understood, and its presence (albeit transient) in the cytoplasm, it would not be surprising if additional substrates for RNases MRP were identified in the future.

RNase MRP and human diseases

In humans, mutations within the RNA component of RNase MRP or the disruption of RNase MRP RNA transcription due to mutations (insertions/duplications) in the promoter region of the RNase MRP RNA gene (RMRP) result in a variety of recessive pleiotropic diseases generally characterized by various degrees of dwarfism and other abnormalities. These diseases include cartilage hair hypoplasia (CHH) (Ridanpaa et al. 2001) and a variety of dysplasias (Kuijpers et al. 2003; Ridanpaa et al. 2003; Bonafé et al. 2005; Thiel et al. 2005).

Incapacitating mutations of the RMRP promoter region are shown to sharply reduce RNase MRP RNA transcription in vitro and result in reduced levels of RNase MRP in patients (Hermanns et al. 2005; Nakashima et al. 2007). Mutations in the promoter region have never been found to be homozygous or in compound heterozygosity with another RMRP promoter mutation (Bonafé et al. 2005), indicating a likely lethality of such a genotype, consistent with the essential role of RNase MRP. On the other hand, incapacitating mutations in the promoter region are always accompanied by mutations within the RNA component of RNase MRP (Bonafé et al. 2005).

Incapacitating mutations within the RNA component of RNase MRP are found in a wide range of positions and may include various substitutions, duplications, insertions, and deletions, typically in phylogenetically conserved regions of RNA (Bonafé et al. 2005; Hermanns et al. 2006; Hirose et al. 2006; Martin and Li 2007, and references therein). The type and severity of clinical manifestations are apparently defined by the type/localization of the mutations in the two affected alleles. A possible correlation between the general localization of the mutations in the RNA component of RNase MRP and the resultant phenotype has been reported (Thiel et al. 2007). Mutations in the RNA component of RNase MRP were reported to interfere with interactions with specific protein components, result in a reduced stability of RNA (likely due to effects on the assembly of this ribonucleoprotein), and/or change the activity/specificity of the enzyme (Bonafé et al. 2005; Hermanns et al. 2005; Thiel et al. 2005, 2007; Nakashima et al. 2007; Welting et al. 2008, and references therein), possibly resulting in a cell cycle delay similar to that seen in yeast (Cai et al. 2002); however, specific mechanisms responsible for pleiotropic diseases caused by RNase MRP mutations in humans are not currently known.


Two types of bacterial RNase P

Bacterial RNase P holoenzyme contains an RNA component and a small protein (Stark et al. 1978; Kole and Altman 1979, 1981; Kole et al. 1980). The RNA component by itself has catalytic activity in vitro under conditions of elevated ionic strength or in the presence of polyamines (Guerrier-Takada et al. 1983); the protein is required for activity at physiological conditions (Kole and Altman 1979).

Based on the secondary structures of their RNA components (Guerrier-Takada and Altman 1984a; James et al. 1988; Brown et al. 1991; Haas et al. 1991, 1994, 1996a; Brown and Pace 1992), bacterial RNases P can be divided into two major types: the most common A-type (ancestral, usually represented by RNase P from E. coli) (Fig. 2A) and B-type (Bacillus, found in low G+C Gram-positive bacteria and usually represented by RNase P from Bacillus subtilis) (Fig. 2B; Haas et al. 1996a). The two types of RNase P demonstrate somewhat distinct biochemical and biophysical properties in vitro (one of the most striking differences being the ability of B-type holoenzymes to dimerize) (Fang et al. 2001; Barrera et al. 2002); however, their RNA components may be interchangeable both in vitro (Guerrier-Takada et al. 1983) and in vivo (Waugh and Pace 1990; Wegscheid et al. 2006).

Conservation and variability in bacterial RNase P RNAs

Sequences of RNA components of RNases P from different bacteria are very diverse (see the RNase P Database, http://www.mbio.ncsu.edu/RnaseP/home.html) (Brown 1999). Despite the overall divergence of sequences, five regions in RNase P RNA demonstrate a high degree of conservation and are termed conserved regions (Figs. 2, ,3,3, CR-I, CR-II, CR-III, CR-IV, CR-V) (Chen and Pace 1997). These regions contain several nucleotides that are nearly absolutely conserved in all RNases P from all domains of life (Chen and Pace 1997; Brown 1999).

The secondary structures of RNA components of bacterial RNases P demonstrate a high degree of phylogenetic conservation: the vast majority of the identified bacterial RNase P RNAs are essentially variants of two major types (A-type or B-type) with variations in the auxiliary elements (which can greatly differ in length or, in some instances, be completely missing) (Brown 1999). A minimized RNase P RNA engineered without the variable elements (Fig. 2C) can cleave pre-tRNA in vitro under conditions of elevated ionic strength (albeit with an ~600-fold decrease in catalytic efficiency), but is not catalytically active at low ionic strength even in the presence of the protein component (Siegel et al. 1996).

Structural domains in bacterial RNase P RNA

As is typical for large structured RNA molecules, the RNA component of bacterial RNase P can be divided into structural domains. There are two structural domains in bacterial RNase P RNA: the specificity domain (S-domain) and the catalytic domain (C-domain) (Fig. 2; Pan 1995; Loria and Pan 1996, 1999). The two domains fold independently of each other and, when combined, can form a bimolecular complex that has the proper specific catalytic activity (Pan 1995; Loria and Pan 1996). The specificity domain is involved in the recognition of the TΨC stem–loop of the substrate pre-tRNA and can bind and properly position the substrate, thus conferring the specificity for pre-tRNA substrates (Loria and Pan 1997; Odell et al. 1998; Mobley and Pan 1999; Qin et al. 2001). The catalytic domain contains the active site, is capable of catalysis, and binds the protein component of RNase P specifically, but by itself has little specificity and affinity for substrates (Odell et al. 1998; Loria and Pan 1999, 2001; Mobley and Pan 1999).

Available structural information on bacterial RNase P RNA

The most detailed information on the structural organization of the RNA component of bacterial RNase P comes from crystallographic studies of specificity domains (A-type, PDB ID 1U9S, resolution 2.9 Å [Krasilnikov et al. 2004]; B-type, PDB ID 1NBS, resolution 3.15 Å [Krasilnikov et al. 2003]), as well as entire RNA components (A-type, PDB ID 2A2E, resolution 3.85 Å [Torres-Larios et al. 2005]; and B-type, PDB ID 2A64, resolution 3.3 Å [Kazantsev et al. 2005]); the crystal structures proved to be in an overall agreement with results of modeling (Harris et al. 1994; Brown et al. 1996; Chen et al. 1998; Massire et al. 1998, and references therein).

Structural organization of the specificity domains

Despite the divergent secondary structures of the specificity domains of the two (A and B) types and the resultant divergence in the overall tertiary folds, both types of the S-domain have a very similar clamp-like opening formed by stacked helical stems P8/P9, P10/P11, and a compact module formed by nonhelical junctions J11/12 and J12/11 (Krasilnikov et al. 2003, 2004). The structural elements forming this opening are universally found in all RNases P, including archaeal and eukaryotic enzymes (Chen and Pace 1997), and contain two of the five conserved regions in RNase P (CR-II, CR-III). Importantly, the RNase P nucleotides that were shown to directly interact with the TΨC loop of the pre-tRNA substrate (LaGrandeur et al. 1994; Loria and Pan 1997; Odell et al. 1998) line this opening in a manner that is practically identical in the two types of S-domain (Krasilnikov et al. 2003, 2004). The shape and the size of the opening, the phylogenetic conservation of the elements forming it, its structural conservation in the two divergent types of the S-domains, and the positioning of the nucleotides involved in direct interactions with the TΨC loop of the pre-tRNA substrate all strongly suggest that this clamp-like opening serves to recognize the TΨC stem–loop of the substrate and that this function is likely to be conserved in RNases P across kingdoms of life (Krasilnikov et al. 2003, 2004, and references therein).

Analysis of biochemical data allowed the modeling of the TΨC stem–loop of tRNA into the clamp-like opening of the specificity domain (Krasilnikov et al. 2004). In this model, the TΨC-loop interacts with the nonhelical module J11/12-J12/11, which is formed by two interleaving RNA strands, each folded into the T-loop RNA folding motif, a motif found in the TΨC-loop itself (Krasilnikov and Mondragon 2003). This RNA–RNA interaction is proposed to be stabilized by the stacking of nucleobases and scattered hydrogen bonding (Krasilnikov et al. 2004).

A structural role for peripheral elements in the specificity domain

In order to form the structurally conserved clamp-like opening, which lies in the core of the specificity domain, the elements forming the opening must be properly positioned relative to each other. This positioning is achieved through the action of auxiliary peripheral elements, which form a three-dimensional buttress serving to provide structural stability to the functionally important core. Interestingly, the major difference between the two types of S-domain is simply in the architecture of this auxiliary buttress. In the A-type RNase P, the structural rigidity of the functionally important substrate-binding region is provided mostly by helical stems P13/P14 forming tertiary interactions (mostly ribose zipper/A-minor interactions) (Cate et al. 1996; Nissen et al. 2001) and base stacking) with stems P8 and P12 (Krasilnikov et al. 2004). In the B-type molecules (Krasilnikov et al. 2003), the P13/P14 stems are absent, and structural support to the core is provided by tertiary interactions of the stem P10.1 (which is not found in the A-type RNase P) with the terminal loop of the P12 stem (tetraloop–tetraloop receptor interaction) (Cate et al. 1996) as well as with stems P7/P10 (ribose zipper/A-minor interaction) (Cate et al. 1996; Nissen et al. 2001). Thus the same goal of stabilizing the functionally important core is achieved through two very architecturally different solutions (Krasilnikov et al. 2004; Westhof and Massire 2004).

Currently available structures of whole-length bacterial RNase P RNAs

An invaluable insight into the structural organization of the RNA component of RNase P was provided by the two crystal structures of the entire RNase P RNAs, which were reported independently and practically simultaneously: the structure of an A-type RNase P RNA from Thermotoga maritima (Torres-Larios et al. 2005) and a B-type molecule from Bacillus stearothermophilus (Kazantsev et al. 2005). While each structure has its own limitations, the two structures are consistent and complement each other.

The crystals of the A-type RNase P RNA (Torres-Larios et al. 2005) allowed tracing of both specificity and catalytic domains. The low (3.85 Å) resolution generally did not allow tracing of the positions of nucleobases in nonhelical regions, but helical regions and phosphate backbones of nonhelical regions could be reliably assigned for most of the molecule, revealing the three-dimensional architecture of the molecule and the tertiary interactions involved in its stabilization (Fig. 4A). The A-type RNase P RNA crystallized as a dimer with two RNA molecules that swapped the strands forming the P6 helix. While it is not likely that this dimer had functional significance, its formation did not cause significant distortion of the structure (Torres-Larios et al. 2005).

Crystal structure of bacterial RNase P RNAs. (A) A-type RNase P from T. maritima (Torres-Larios et al. 2005). (B) B-type RNase P from B. stearothermophilus (Kazantsev et al. 2005). Individual structural elements are color-coded (A, B). (C) A-type RNase ...

Crystals of the B-type RNase P RNA (Kazantsev et al. 2005) diffracted to a higher resolution (3.3 Å), providing more-detailed information on most of the molecule, including nonhelical regions (Fig. 4B). Unfortunately, crystallization apparently distorted the localization of the specificity domain, swinging it away from the catalytic domain and resulting in substantial disorder in the S-domain (Torres-Larios et al. 2006, and references therein). Nevertheless, the structure of the B-type RNase P RNA provides invaluable insight into the intricate details of the structural organization of the catalytic domain.

Comparison of the catalytic domains in the two types of RNase P RNA (Torres-Larios et al. 2006) shows that the overall RNA fold is very well conserved, and, as in the specificity domain, the major difference between the two molecules is in the arrangement of the peripheral elements that appear to serve to stabilize the tertiary fold (Kazantsev et al. 2005; Torres-Larios et al. 2005, 2006).

Divalent ions (naturally magnesium) play crucial roles in RNase P RNA folding (Baird et al. 2007, 2010; Qu et al. 2008; Kazantsev et al. 2009, and references therein) and catalysis (Kirsebom and Trobro 2009, and references therein). Due to the insufficient resolution of available crystal structures, the precise location of the magnesium ions could not be reliably determined, although valuable information was obtained using anomalous scattering by other ions (Krasilnikov et al. 2004; Kazantsev et al. 2009), as well as by a combination of NMR and extended X-ray absorption fine structure (EXAFS) spectroscopy (Koutmou et al. 2010a) and other approaches (Christian et al. 2006; Getz et al. 2007, and references therein).

Models of RNase P RNA/tRNA complexes

There are currently no published structures of RNase P RNA in a complex with a substrate or product. However, the availability of biochemical data and structural information on RNase P RNA alone allows for the construction of reasonably detailed models of such complexes. Two models based on a combination of biochemical data and the available RNase P RNA crystal structures, A-type (Torres-Larios et al. 2005) and B-type (Kazantsev et al. 2005), are available. One model (Torres-Larios et al. 2005) was obtained by docking tRNA to the S-domain (described above) (Krasilnikov et al. 2004) without using information on the interactions between tRNA and the C-domain. Such docking (Fig. 4C) placed the cleavage site in the immediate vicinity of the general location of the putative catalytic site, although some minor adjustments to the relative positioning of the tRNA and C-domain would be needed to accurately reflect known interactions, likely indicating a degree of structural flexibility in RNase P RNA (Torres-Larios et al. 2005). The second model (Fig. 4D; Kazantsev et al. 2005; Kazantsev and Pace 2006) made use of the more-detailed structural information on the C-domain of the B-type RNase P RNA for the docking of tRNA to the C-domain; the known interactions with the S-domain could not be modeled (apparently because of the distorted orientation of the S-domain in the B-type structure). Even though the two models are produced using different and essentially independent sets of data, there is a remarkable similarity between them (Fig. 4C,D; Torres-Larios et al. 2006), indicating that they likely reflect the real juxtaposition of tRNA and RNase P RNA. For more details on the structural organization of the RNA component of bacterial RNase P, see Torres-Larios et al. (2006).

Available crystallographic data provide a general understanding of RNase P RNA architecture and allow the creation of models of the enzyme–substrate complex. However, information crucial for the understanding of the details of the mechanism of RNase P catalytic action is still not available, and further investigation of the structure of RNase P RNA and enzyme–substrate/enzyme–product complexes is required.


The bacterial RNase P protein is an essential component of the holoenzyme

The protein component of the bacterial RNase P holoenzyme, a small basic protein, is required for the catalytic activity at physiological conditions and is essential for the survival of the bacterial cell (Schedl and Primakoff 1973; Kole et al. 1980; Guerrier-Takada et al. 1983; Kirsebom et al. 1988; Reich et al. 1988; Gossringer et al. 2006, and references therein).

Despite its small size (~10% of the holoenzyme mass), the protein component of bacterial RNase P plays multiple and diverse roles in the holoenzyme. It is suggested to influence the function of the holoenzyme by enhancing substrate binding through the reduction of electrostatic repulsion (Reich et al. 1988), by altering substrate recognition (Peck-Miller and Altman 1991; Liu and Altman 1994; Loria et al. 1998; Sun et al. 2006, 2010), by helping to stabilize the active RNA conformation (Westhof et al. 1996; Gopalan et al. 1997; Kim et al. 1997; Buck et al. 2005a), and by aiding substrate recognition and helping catalysis by discriminating between substrate and product through the binding to the 5′ leader sequence of pre-tRNA (Crary et al. 1998; Kurz et al. 1998; Niranjanakumari et al. 1998; Rueda et al. 2005; Sun et al. 2006; Hsieh and Fierke 2009; Koutmou et al. 2010b), as well as by enhancing metal ion activity in the active site (Kurz and Fierke 2002; Sun and Harris 2007); the presence of the protein component can also alleviate effects of deleterious mutations in the RNA component (Lumelsky and Altman 1988).

Available structures of bacterial RNase P proteins

The structures of the protein components of bacterial RNases P of both A- and B-types have been determined: the 2.6 Å structure of the protein from B. subtilis (B-type, PDB ID 1A6F) (Stams et al. 1998); the solution structure of the protein from Staphylococcus aureus (B-type, PDB ID 1D6T) (Spitzfaden et al. 2000); and the 1.2 Å structure of Thermotoga maritima protein (A-type, PDB ID 1NZ0) (Kazantsev et al. 2003).

Despite divergent sequences, the protein components of the A- and B-types of bacterial RNase P have very similar folds (Kazantsev et al. 2003); the similarity of the folds of the protein components of the two types of RNase P is consistent with the fact that their protein components are interchangeable (Guerrier-Takada et al. 1983; Waugh and Pace 1990; Wegscheid et al. 2006).

The structural organization of the protein component of bacterial RNase P

The protein component of bacterial RNase P has a globular αβββαβα fold (Fig. 5A) that contains a rare left-handed βαβ crossover and resembles βββαβα folds found in RNA-binding proteins of the translational apparatus: the C-terminal domain of ribosomal protein S5 and domain IV of elongation factor G (EF-G) (Stams et al. 1998).

Crystal structures of bacterial and archaeal RNase P proteins. (A–F) (Red) α-Helices; (yellow) β-strands; (green) loops. (A) Crystal structure of bacterial RNase P protein (PDB ID 1NZ0). Locations of the metal-binding loop (gray), ...

An analysis of more recent structures reveals additional similarly folded proteins, notably, archaeal exosome complex exonuclease Rrp42 (PDB ID 2BA1, chain H). This exosomal exoribonuclease contains a domain having a βββαβα topology with left-handed βαβ crossover that is remarkably similar to the one found in bacterial RNase P protein, possibly providing additional clues to the evolutionary relationships of the protein component of RNase P (AS Krasilnikov, unpubl.).

The protein component contains three regions that have been proposed to interact with RNA (Stams et al. 1998): a conserved (Jovanovic et al. 2002) sequence termed the RNR motif; the central cleft; and a variable loop that contains a cluster of negatively charged residues (while the protein in general is highly basic), termed the metal-binding loop (Fig. 5A).

Interactions between the protein and RNA components of bacterial RNase P

Interactions between the protein component of bacterial RNase P and its RNA component have been extensively studied (for review, see Hsieh et al. 2004; Smith et al. 2007), but the high-resolution structure of the RNase P holoenzyme is yet to be reported. The wealth of available biochemical and phylogenetic information—and, more recently, available structures of RNA and protein components—allow building relatively detailed models of the holoenzyme and holoenzyme–substrate complexes (Niranjanakumari et al. 1998, 2007; Christian et al. 2002; Tsai et al. 2003; Buck et al. 2005b; Koutmou et al. 2010b, and references therein).

The general location of the protein component on RNase P RNA has been established (Buck et al. 2005b; Niranjanakumari et al. 2007, and references therein). The protein component binds to a well-conserved area located in the catalytic domain in a general vicinity of the putative active site and appears to be positioned to contact a pre-tRNA substrate, including the 5′ leader (Fig. 4C,D; Buck et al. 2005b). The patch protected by the protein component spans several secondary structure elements, allowing the protein component to influence the general conformation of the catalytic domain, although the conformational change appears to be modest (Buck et al. 2005b, and references therein). The general orientation of the protein component relative to the RNA component could be determined using available biochemical data (Tsai et al. 2003; Buck et al. 2005b, and references therein); more recently, a library of protein variants that were modified at specific positions for photocrosslinking and hydroxyl-radical-directed cleavage assays has allowed obtaining more-detailed information on the protein's position, suggesting a somewhat different protein orientation and a shorter distance to the cleavage site compared with older models (Niranjanakumari et al. 2007). Nevertheless, the models are reasonably consistent (considering their low resolution) (for review, see Smith et al. 2007). However, high-resolution structural information is necessary to reveal the specifics of the RNA–protein interactions and determine the role of the protein in the organization of the catalytic center in the holoenzyme.


Two types of archaeal RNase P

Known archaeal RNase P holoenzymes consist of an RNA component and at least four proteins (Hall and Brown 2002; Hartmann and Hartmann 2003; Kouzuma et al. 2003; Fukuhara et al. 2006; Pulukkunat and Gopalan 2008).

Similar to their bacterial counterparts, archaeal RNase P RNA components demonstrate a high degree of phylogenetic conservation at the level of secondary structure and have a well-conserved core with varying peripheral elements (Brown 1999). Based on the secondary structures of their RNAs, all known archaeal RNases P can be divided into two types: the A-type (ancestral, the majority of archaeal RNases P) (Fig. 2D) and the M-type (represented by Methanococcus RNases P) (Fig. 2E; Harris et al. 2001, and references therein).

The A-type archaeal RNase P

The most common A-type archaeal RNase P RNA resembles the most common A-type of bacterial RNase P (Haas et al. 1996b; Harris et al. 2001). The major differences between typical A-type bacterial and A-type archaeal RNase P RNAs are the absence of stems P13/P14 in archaeal RNAs; the presence of conserved and elaborate structural features incorporated into the P12 stem in archaeal RNAs; and the absence of the P18 stem in archaeal RNAs. It should be noted that the differences listed above are typical, but not universal: some bacterial RNase P RNAs are also missing P13/P14 but often have elaborate P12 stems, and P18 is absent in some bacteria (Brown 1999; Harris et al. 2001, and references therein). Overall, the A-type archaeal RNase P RNA appears to retain many, but not all, peripheral elements involved in the stabilization of the essential and phylogenetically conserved core (Chen and Pace 1997) of the bacterial RNase P.

A-type archaeal RNase P RNAs can be catalytically active without any protein components, but this activity requires extremely high ionic strengths (maximal activity was observed in 2M–3M ammonium acetate supplemented with 200–500 mM Mg2Cl) (Pannucci et al. 1999; Kouzuma et al. 2003; Tsai et al. 2006); biochemical properties of A-type RNase P RNAs were found to be similar to the properties of “minimized” bacterial RNase P (Siegel et al. 1996), which lack peripheral elements involved in the stabilization of the tertiary structure, indicating that A-type archaeal RNase P RNAs contain all elements required for substrate cleavage but are structurally defective without protein components (Pannucci et al. 1999). Relatively minor changes in the catalytic domain toward the bacterial RNase P consensus or a replacement of the archaeal S-domain with a bacterial S-domain substantially increase the catalytic activity of type A archaeal RNase P RNA (Li et al. 2009).

The M-type archaeal RNase P

The M-type archaeal RNase P RNA (Harris et al. 2001) is missing almost all of the peripheral structural elements involved in the stabilization of the tertiary structure of bacterial RNase P RNA (Fig. 2E) and in this sense is closer to the eukaryotic (Fig. 3A,B; see the next section) than to the bacterial RNase P. M-type RNase P RNAs do not exhibit any noticeable catalytic activity in the absence of proteins (Pannucci et al. 1999, and references therein). However, all essential core elements are still present in the M-type RNase P RNA, and its catalytic domain is capable of catalysis when the archaeal specificity domain is replaced with a bacterial one (which echoes the situation with the A-type archaeal RNase P) (Li et al. 2009) or when the substrate is tethered in cis (Pulukkunat and Gopalan 2008).

Proteins in archaeal RNase P holoenzymes

A comparison of the catalytic properties of the bacterial RNase P RNAs (which have an elaborate network of tertiary interactions serving to stabilize their structures) (Kazantsev et al. 2005; Torres-Larios et al. 2005) with their archaeal counterparts (which are apparently missing some [A-type] or most [M-type] of these interactions), clearly indicates the importance of RNA–RNA tertiary interactions for the activity of the RNA components in the absence of proteins. It is likely that one of the roles for the more complex protein moiety in archaeal RNase P is to compensate for missing RNA–RNA interactions by providing alternative protein-mediated tertiary interactions.

Similar to the case of bacterial RNase P, the protein moiety of archaeal RNase P is required for activity at low ionic strengths (Tsai et al. 2006, and references therein). Initial analysis of the protein components of archaeal RNase P has identified four archaeal RNase P proteins. These proteins are homologous to the protein components of eukaryotic RNase P Pop4, Pop5, Rpp1, and Rpr2 (Table 1; Hall and Brown 2002).

More recent studies indicate that at least some archaeal RNases P may possess an additional, fifth protein component: a ribosomal protein L7Ae, which is related to eukaryotic RNase P protein Pop3 (Fukuhara et al. 2006; Lai et al. 2010). The putative fifth protein component, the ribosomal protein L7Ae, was reported to increase the thermal stability of archaeal RNase P (Fukuhara et al. 2006; Terada et al. 2006), possibly by stabilizing the tertiary structure.

Protein components of the archaeal RNase P act in pairs

Reconstitution of highly active A-type archaeal RNases P from the RNA component and individual proteins has been reported (Boomershine et al. 2003; Kouzuma et al. 2003; Terada et al. 2006; Tsai et al. 2006). Analysis of the influence of the protein components on the activity of partially assembled RNase P ribonucleoprotein complexes shows that the four established protein components act in pairs: aPop4 + aRpr2 and aPop5 + aRpp1 (Tsai et al. 2006), consistent with the results of the two-hybrid analysis of protein–protein interactions performed for Pyrococcus horikoshii OT3 proteins in yeast (Kifusa et al. 2005).

The two protein pairs act in a cooperative manner: the aPop5 + aRpp1 pair is suggested to interact with and stabilize the catalytic domain (Tsai et al. 2006; Pulukkunat and Gopalan 2008; Honda et al. 2010), whereas the aRpr2 + aPop4 pair is suggested to be involved in the stabilization of the specificity domain while interacting with aPop5 + aRpp1 (Xu et al. 2009; Honda et al. 2010). The available results of studies aimed at the localization of the protein-binding sites on RNA (Fukuhara et al. 2006; Xu et al. 2009) also appear to be consistent with the roles of the two protein pairs. Kinetic studies performed using partially reconstituted RNase P holoenzymes (Tsai et al. 2006) show that the two protein pairs contributed to the activity differently: the aPop5 + aRpp1 pair (but not the aPop4 + aRpr2 pair) enhances kcat, suggesting that the aPop5 + aRpp1 pair plays a significant role in cleavage and/or product release; the two protein pairs reduced Km in a similar way, while the presence of both pairs decreased Km in a synergistic manner. Thus, the available results on the roles of the two protein pairs in archaeal RNase P appear to be consistent.

Available structures of the protein components of archaeal RNase P

Structures of all individual protein components of archaeal RNase P have been determined:

In addition, several structures of binary protein–protein complexes are also available:

Folds of archaeal RNase P proteins

The folds of archaeal RNase P proteins are distinct from that of the bacterial RNase P protein (Fig. 5A–F). Protein aRpp1 (Fig. 5D) folds into an α/β barrel structure resembling the TIM barrel (Takagi et al. 2004); aRpr2 (Fig. 5E) is a zinc-binding protein containing a nucleic acid-binding zinc-ribbon motif (Qian et al. 1993); aPop4 (Fig. 5F) is a member of the OB-fold family of nucleic acid-binding proteins (Theobald et al. 2003).

Protein aPop5 (Fig. 5B) and the putative component aPop3 (Fig. 5C) are the only two proteins somewhat resembling the bacterial RNase P protein, adopting general α/β sandwich folds; however, the structural organizations of these three proteins are very different and the connectivity between somewhat similarly positioned secondary structure elements is distinctly divergent. The loose similarity of the bacterial RNase P protein and some of the archaeal ones may, in principle, explain the observed activation of archaeal RNase P RNA by the bacterial RNase P protein (Nieuwlandt et al. 1991; Pannucci et al. 1999).

The pair aPop5 + aRpp1 from P. horikoshii formed a heterotetramer in solution; this heterotetramer was proposed to be physiologically relevant, resulting in the dimerization of the RNase P holoenzyme (Kawano et al. 2006); however, the existence of such RNase P dimers was not proven. The surface electrostatic potential distribution for the aPop5 + aRpp1 heterotetramer reveals positively charged areas possibly involved in interactions with the RNA component and/or the substrate; however, details of such interactions are not currently known.

The surface of the aPop4 + aRpr2 heterodimer (Fig. 5G; Honda et al. 2008; Xu et al. 2009) contains patches of phylogenetically conserved basic residues (Fig. 5H), which may constitute an RNA-binding surface (Xu et al. 2009); however, details of RNA–protein interactions are not known.

A high-resolution structure of the archaeal RNase P holoenzyme is required to provide detailed information on the RNA–protein and protein–protein interactions in archaeal RNase P. Such a structure would provide important evolutionary clues and substantially advance our understanding of the more complex eukaryotic enzymes.


Eukaryotic RNases P/MRP are more complex than bacterial or archaeal RNases P

Eukaryotes possess an additional enzyme closely related to RNase P, namely, RNase MRP. With minor exceptions, both RNase P and RNase MRP were found in practically all eukaryotes analyzed (Piccinelli et al. 2005; Rosenblad et al. 2006).

The two enzymes are considerably more complex than bacterial or archaeal RNases P. The best-studied examples of eukaryotic RNases P/MRP are human and S. cerevisiae enzymes.

The protein moiety of S. cerevisiae RNase P contains nine known protein components ranging in size from 15 to 100 kDa (Table 1). The protein moiety of yeast RNase MRP has a very similar composition: out of its 10 proteins, eight are common with RNase P (Table 1). All known protein components of yeast RNases P/MRP are essential for the functions of these enzymes and for the survival of the cell (Lygerou et al. 1994; Schmitt and Clayton 1994; Chu et al. 1997; Dichtl and Tollervey 1997; Stolc and Altman 1997; Chamberlain et al. 1998; Salinas et al. 2005).

Conserved elements in eukaryotic RNase P RNAs

Secondary structures of RNA components of eukaryotic RNase P (Fig. 3A,B) resemble those of bacterial and archaeal RNases P and have the same major conserved elements (Chen and Pace 1997); however, peripheral elements are divergent and elements involved in the stabilization of the tertiary structure in bacterial RNases P are missing. Consistent with that, while bacterial RNase P becomes more compact in the presence of Mg2+ (presumably due to the stabilization of the tertiary fold) (Baird et al. 2010), eukaryotic RNase P RNA alone was shown not to be capable of forming a more compact structure in the presence of Mg2+ (Marquez et al. 2006).

Eukaryotic RNase P RNAs contain parts similar to the catalytic domain (C-domain) and the specificity domain (S-domain) of bacterial RNase P (Pan 1995; Loria and Pan 1996, 1999), and, drawing an analogy with bacterial RNase P, it is common to consider these parts to be domains in eukaryotic enzymes (Fig. 3A,B).

A universal essential feature found in practically all eukaryotic RNases P, but not in bacterial or archaeal enzymes, is the helix–loop–helix subdomain P3, which replaces the P3 stem found in bacterial and archaeal RNase P (Figs. 2, ,3;3; Lindahl et al. 2000; Ziehler et al. 2001; Piccinelli et al. 2005). This subdomain specifically binds protein components Pop6 and Pop7 (Pluk et al. 1999; Perederina et al. 2007; Welting et al. 2007), and, likely, Pop1 (Ziehler et al. 2001). The P3 subdomain is suggested to act as a protein-binding hub in the protein-rich eukaryotic enzymes (Ziehler et al. 2001; Perederina et al. 2010b). Structural information on the yeast P3 RNA subdomain in a complex with protein components Pop6 and Pop7 has recently became available (Fig. 6; Perederina et al. 2010a,b). The P3 subdomain and proteins bound to it (directly or indirectly) are suggested to be in a position to compensate for the loss of RNA components involved in the stabilization of the tertiary structure in bacterial RNase P (Perederina et al. 2010b).

Crystal structure of S. cerevisiae P3 RNA subdomain in a complex with proteins Pop6 and Pop7 (Perederina et al. 2010b). (Red and pink) RNA; (blue) Pop6; (green) Pop7; (dotted line) missing or unresolved regions. In the orientation shown, the distal terminal ...

The RNA component is the catalytic moiety in eukaryotic RNase P

The RNA component is shown to be the catalytic moiety of eukaryotic RNase P (Thomas et al. 2000b; Kikovska et al. 2007); however, the cleavage rate observed for human RNase P RNA without proteins is five to six orders of magnitude lower than that for bacterial RNase P RNA (Kikovska et al. 2007). This dramatic decrease in catalytic activity is likely to be due to the absence of essential structural elements involved in the stabilization of the catalytically active conformation of RNA that are found in bacterial but not eukaryotic enzymes, similar to the case of archaeal RNases P (Gopalan 2007).

Protein components affect RNA folding in eukaryotic RNase P

Protein components appear to play a crucial role in the folding of eukaryotic RNase P RNA, which is in contrast with bacterial enzymes where the structural effects of protein binding appear to be important but modest (Buck et al. 2005b, and references therein). An analysis of the results of footprinting performed on yeast RNase P holoenzyme (Esakova et al. 2008) shows that the footprinting pattern observed for the phylogenetically conserved parts of the specificity domains CR-II and CR-III (a region involved in interactions with the TΨC-loop of pre-tRNA substrate) (Krasilnikov et al. 2004, and references therein) is consistent with the conformation found in bacterial RNase P RNA (Krasilnikov et al. 2003, 2004), while in deproteinated samples, this region does not appear to be properly folded. Thus, the protein moiety appears to be required for the folding of at least some of the key parts of RNA. At the same time, S. pombe RNase P RNA was reported (Marquez et al. 2006) to be capable of the specific binding of tRNA without any proteins (albeit much less efficiently than E. coli RNase P RNA), and crosslinking studies indicated that at least some segments of the catalytic domain of S. pombe RNase P RNA might be folded even without proteins (Marquez et al. 2006). It is possible that in eukaryotic RNase P RNA the fold of the specificity domain (and/or its position relative to the catalytic domain) is more sensitive to the absence of protein components than the fold of the catalytic domain, similar to the case of archaeal RNase P RNA (Pulukkunat and Gopalan 2008; Li et al. 2009). In this scenario, the observed low-efficiency binding of tRNA by the RNA-only eukaryotic RNase P (Marquez et al. 2006) can be explained by its interactions with the catalytic domain.

Parallels between the RNA components of RNase MRP and eukaryotic RNase P

In RNase MRP, the RNA component has a part (denoted as Domain 1) (Fig. 3C,D) closely resembling the C-domain of the RNA component of eukaryotic RNase P (Fig. 3A,B). The two domains share the general secondary structure and the locations of several phylogenetically conserved nucleotides. Moreover, the protein-binding P3 subdomains in yeast RNase MRP and RNase P can be swapped (Lindahl et al. 2000), further emphasizing the similarity of these parts in RNase P and RNase MRP. The similarity of Domain 1 of RNase MRP to the catalytic domain of RNase P strongly suggests that these parts play similar roles in the two enzymes and that the RNA component is the catalytic moiety in RNase MRP as it is in RNase P, although no experimental confirmation of catalytic activity of RNase MRP RNA without proteins has been reported.

RNase MRP has no parts resembling the specificity domain of RNase P; instead, RNase MRP contains a divergent segment denoted as Domain 2 in Figure 3, C and D. (It should be noted that the term “domain” has a very loose meaning when applied to RNase MRP RNA and does not mean that these “domains” are truly independent structural or functional entities [as they are in bacterial RNase P]; rather, it merely serves to emphasize the parallels between RNases P and MRP.) The divergence of the specificity domain in RNase P and the corresponding part in RNase MRP is consistent with the distinct substrate specificities of the two enzymes.

Domains 2 in RNase MRPs from different organisms differ significantly; however, they contain a phylogenetically well-conserved element with the consensus sequence GARAR (Fig. 3C,D; Lopez et al. 2009, and references therein). Phylogenetic data suggest that this conserved GARAR element may form a pentaloop that closes a short stem “P8” (for review, see Lopez et al. 2009); however, holoenzyme footprinting results (Esakova et al. 2008) indicate that this putative loop “P8” is not formed in yeast and, accordingly, it is not shown in Figure 3.

Potential roles for protein components in RNase MRP and eukaryotic RNase P

The roles of protein components in eukaryotic RNase P and RNase MRP are not clear, and the reasons for the dramatic increase in the complexity of the protein moieties remain a mystery. In addition to the roles played by the protein moiety in bacterial RNase P, the protein components are almost certainly involved in the stabilization of the tertiary structure of the catalytic RNA component, compensating for the loss of RNA–RNA tertiary interactions (although four or five proteins homologous to the archaeal RNase P proteins should be sufficient for that purpose). The increased complexity of the protein moiety is suggested to allow the processing of a broader range of substrates (Marvin and Engelke, 2009). It is also reasonable to suggest that the more complex intracellular environment of the eukaryotic cell demands better specificity of substrate recognition, which can be provided by fine-tuning the geometry of the substrate-binding interface, and this is easier to accomplish using proteins (nucleotides are substantially more coarse building blocks than amino acids). Specific protein components may be required for the intracellular localization of the complexes, and some of the protein components may, in principle, be responsible for interactions with other parts of the cellular machinery or be involved in the regulation of the activity of RNases P/MRP. Reported properties of individual protein components appear to be consistent with these roles (for review, see Jarrous 2002). However, exact roles of individual protein components and mechanisms of their action are not currently clear.

Available structural information on RNase MRP and eukaryotic RNase P

Structural organizations of eukaryotic RNase P and RNase MRP are not clear. Structural studies of the holoenzyme are complicated by a relatively low abundance of these complexes. (It was estimated that yeast contains about 400 molecules of RNase P per cell [Srisawat and Engelke 2001, and references therein]; the amount of RNase MRP is similar [Esakova et al. 2008; ME Schmitt, pers. comm.].) Studies of human enzymes may be further complicated by the possible dynamic nature of the complexes or the variability of their compositions (Welting et al. 2006).

The available crystal structures of bacterial RNase P provide a glimpse of the structural organization of some phylogenetically conserved parts in eukaryotic enzymes: CR-II and CR-III regions can be expected to fold into two interleaving T-loop motifs (Krasilnikov et al. 2004), and the similarity between the bacterial and eukaryotic C-domains allows making detailed predictions regarding the structural organization of parts of the C-domain in eukaryotic RNase P (Marquez et al. 2006) and, by inference, in RNase MRP.

High-resolution structural information on eukaryotic RNase P and RNase MRP is available only for the yeast P3 subdomain that was recently crystallized in complex with protein components Pop6 and Pop7 (Fig. 6; Perederina et al. 2010a,b). The P3 subdomain RNA folds into two nearly coaxial helical regions separated by an internal loop. The fold of this loop is stabilized predominantly by interactions with proteins and the stacking of RNA nucleobases: no canonical or noncanonical base-pairing is observed in this region. The protein components Pop6 and Pop7 have very divergent sequences but form similar folds, closely resembling nucleic acid-binding proteins of the Alba family (Wardleworth et al. 2002; Aravind et al. 2003). In spite of the structural similarity, the distributions of the charged residues on the proteins' surfaces are very divergent, and the two proteins interact with the RNA component in different manners (Perederina et al. 2010b). Pop6 enters the major groove of the distal helical stem of the P3 RNA subdomain (Fig. 6); in addition, it interacts with several nucleotides of the single-stranded loop. Pop6 appears to fold in the absence of Pop7; however, it does not bind to RNA unless it forms a heterodimer with Pop7 (Perederina et al. 2007). Interactions of Pop7 with RNA are more extensive than those for Pop6 and involve both strands of the loop part of the P3 RNA subdomain (Perederina et al. 2010b). Pop7 requires both Pop6 and RNA for folding. In addition to Pop6 and Pop7, the P3 RNA subdomain is expected to bind to another protein component, Pop1 (Ziehler et al. 2001), and, possibly, others. The P3 subdomain in human RNases P/MRP is likely to have a similar structural organization (Hands-Taylor et al. 2010; Perederina et al. 2010b).

Eukaryotic protein components Pop3, Pop4, Pop5, Rpp1, and Rpr2 have apparent archaeal homologs with known structures (Table 1). Structures of archaeal proteins can provide insight into the structural organization of these eukaryotic RNase P/MRP proteins, although eukaryotic proteins tend to be larger and may play additional roles (Li and Altman 2001; Jiang and Altman 2002).

Information on the influence of the protein moiety on the conformation of the RNA component and on the general localization of the protein moiety on RNA was obtained using footprinting analysis of RNase P (Tranguch et al. 1994; Esakova et al. 2008) and RNase MRP (Esakova et al. 2008) holoenzymes. The results obtained for the C-domain of RNase P and Domain 1 of RNase MRP were strikingly similar, suggesting a common structural organization of the putative catalytic parts of the two holoenzymes.

Available low-resolution structural information on interactions between individual components of eukaryotic (human and S. cerevisiae) RNase P and RNase MRP is based primarily on the results of UV crosslinking (Pluk et al. 1999; Jiang et al. 2001), yeast two- or three-hybrid studies (Jiang and Altman 2001; Jiang et al. 2001; Houser-Scott et al. 2002), and GST pull-down experiments (Welting et al. 2004; Aspinall et al. 2007). Low-resolution maps describing both RNA–protein and protein–protein interactions were suggested for yeast (Houser-Scott et al. 2002; Aspinall et al. 2007) and human (Welting et al. 2004, 2006) RNases P/MRP. However, the interpretation of the results can be complicated by the fact that both protein subunits and RNA may require interacting partners to form physiologically relevant folds: for example, most protein components of yeast complexes are not soluble or tend to form soluble aggregates when expressed alone. In addition, most protein components are highly basic and thus prone to nonspecific RNA binding, which can be aggravated further by protein misfolding. Mapping interactions in the context of a partially reconstituted complex should, in principle, give more consistent results, but obtaining structurally homogeneous reconstituted complexes is challenging. (Partial reconstitution of a catalytically active human RNase P from the RNA component and refolded proteins hPop4 and hRpr2 has been reported [Mann et al. 2003], but the complex does not appear to be structurally homogeneous.) Mapping interactions in the context of holoenzymes is a viable alternative.


Substantial progress has been made toward understanding the structural organization and the mechanism of action of bacterial RNase P, but the real understanding of RNase P catalysis is yet to be gained. The results of the crystallographic studies are expected to clarify the role of the protein moiety in the bacterial RNase P holoenzyme and shed light on the details of the enzyme–substrate interactions. High-resolution structural data on the enzyme–substrate complex will be needed to pinpoint the positions of the metal ions crucial for catalysis and identify the RNA elements involved in their coordination; the characterization of the structural changes in RNase P associated with substrate binding and product release will be another challenge.

The details of the structural organization of the more complex archaeal RNase P and eukaryotic RNases P/MRP are starting to emerge, but the roles of their individual components and the reasons for the increased complexity of their protein moieties are still poorly understood, especially for the eukaryotic enzymes. It is likely that novel functions for both RNase P and RNase MRP will be identified and characterized. A deeper understanding of the structure and function of eukaryotic enzymes of the RNase P/MRP family should shed light on the greatest RNase P mystery: the nearly universal conservation of its catalytic RNA moiety through billions of years of evolution.


We thank Phil Bevilacqua, Alfonso Mondragón, Tao Pan, and Mark Schmitt for valuable comments and suggestions. This work was supported by NIH Grant GM085149 to A.S.K.


Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.2214510.


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