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Evolution of Telomere Binding Proteins


* Martin P. Horvath—Biology Department, University of Utah, 257 S 1400 E, Salt Lake City UT 84112-0840, USA. Email: ude.hatu.ygoloib@htavroh

Telomere binding proteins provide essential functions for chromosome maintenance in most eukaryotes and consequently are well suited for analysis in the context of evolution. This review focuses on patterns gleaned from structural and functional characterization of telomere proteins that reveal contrasting evolutionary histories for double-stranded and single-stranded DNA-binding protein families. The myb-like/homeodomain DNA-binding motif is ubiquitous among members of the double-stranded telomere DNA-binding protein family which includes Rap1 and Taz1 in yeast, TRF1 and TRF2 in vertebrates, as well as putative plant-specific telomere proteins, TBP1, TRP1 and Smh1. In this myb-motif family, strong purifying selection has preserved amino-acid sequence among distantly related lineages. Accessory domains linked with the myb-like DNA-binding domain define distinct lineages, indicating that the myb motif was probably recruited multiple times from a reserve of more ancestral forms functioning as transcription factors. The oligonucleotide/oligosaccharide/oligopeptide-binding (OB)-fold is universally found in members of the second class of telomere binding proteins that recognize and bind T/G-rich telomere sequences in the form of single-stranded DNA. Examples of proteins in this class include TEBP-α and TEBPβ from ciliated protozoa, Cdc13 from budding yeast, and Pot1 which is widely distributed in fission yeast, vertebrates and plants. For these OB-fold proteins, rapid divergence at the amino-acid sequence level has all but erased traces of common ancestry. Homology is apparent, however, when comparing three-dimensional structures and functional characters. Sequence alignments consistent with these structural comparisons provide a tentative glimpse of deeply rooted lineages that likely emerged from the general single-stranded DNA-binding proteins dedicated to DNA replication and repair. Interaction networks among telomere DNA-binding proteins and their associated interacting partners hint at further common patterns and innovations encountered during the evolution of telomere capping complexes.


Telomere binding proteins recognize the short tandem repeats characterizing telomere DNA,1 and are essential for stable chromosome maintenance as reflected in the precipitous genome-destabilizing outcomes following gene deletion and over-expression of mutant alleles (reviewed in ref. 2). The nucleoprotein complexes formed upon association of telomere binding proteins with telomere DNA distinguish natural chromosome ends from double-stranded breaks and thereby protect chromosome termini from inappropriate end-to-end ligation. Additionally, telomere binding proteins recruit and regulate telomerase to ensure an appropriate length of structural DNA is maintained as a buffer against loss of genetic information stored in genes close to the ends of linear chromosomes. Recent reviews of telomere binding proteins from yeast and vertebrates have focused on telomere homeostasis and the relationship between these proteins and telomerase and DNA repair pathways.2,3 The emphasis of this chapter will be on the evolution of these important proteins. Questions addressed include “What are the origins of telomere end binding proteins?” and “What are the functions and interactions among telomere proteins predicted by analogy with divergent systems?”

Telomere binding proteins can be broadly divided into two classes on the basis of double-stranded versus single-stranded DNA-binding specificity. DNA-binding specificity correlates with folding motifs particular to each class, with the myb-like/homeodomain motif dictating double-stranded DNA recognition and the OB-fold proteins directed towards single-stranded telomere DNA. This review begins with an introduction to the structures of the myb-like motif and the OB-fold since recent insights regarding evolution of telomere binding proteins rely on relationships inferred from three-dimensional structures of these DNA-binding elements. The origins of double-stranded and single-stranded telomere DNA-binding proteins are then pursued followed by a discussion of cooperative interaction networks characterizing telomere-capping systems.

Protein Folding Motifs for Binding Telomere DNA

Structural biology has been particularly important for inferring evolutionary relationships among telomere binding proteins.4 Crystal structures of the DNA-binding domain of Rap1 from yeast and the telomere end binding protein (TEBP) from Sterkiella nova (formerly Oxytricha nova) in complex with cognate double-stranded and single-stranded telomere DNA, respectively, provided the first high-resolution views of telomere proteins in action.5,6 Since then the structures of several DNA-binding domains or protein-protein interaction domains derived from telomere binding proteins have been determined (see Table 1). The structural architecture of telomere proteins with an emphasis on DNA-protein interactions has been previously reviewed.7 In this section, the basic structural elements of telomere protein DNA-binding domains are summarized so as to provide a foundation for understanding evolutionary analysis of telomere binding proteins.

Table 1. Telomere binding protein structures.

Table 1

Telomere binding protein structures.

The Homeodomain/Myb-Like Motif

The homeodomain/myb-like motif is found in all telomere binding proteins that recognize double-stranded telomere DNA. The myb motif is named after the transcription factor c-Myb, a proto-oncogene which regulates differentiation and proliferation during hematopoiesis.8 The myb-fold consists of three a-helices arranged in an orthogonal bundle around an independent hydrophobic core (Fig. 1). The third helix presents residues that make sequence-specific contacts with bases in the major groove of B-form DNA.5,9,10 For telomere proteins, these DNA-recognition residues are especially well conserved and define the so-called telobox sequence feature.11,12 In TRF1 and TRF2 the DNA-recognition helix is augmented by an N-terminal tail (a in Fig. 1), particular to the homeodomain superfamily, that makes DNA contacts in the adjacent minor groove.10

Figure 1. Myb/homeodomain-DNA complex.

Figure 1

Myb/homeodomain-DNA complex. One of the two DNA-binding domains of the human TRF2 dimer (pdb id 1w0u) is represented with its three α-helices as ribbons. The C-terminal helix 3 fits within the major groove of double-stranded telomere repeat DNA where (more...)

The different architectures of DNA-binding domains constructed from myb-like motifs (Fig. 2) define distinct myb-like protein families. In the DNA-binding domain of c-Myb, three imperfect tandem repeats of the three-helical orthogonal bundle contribute to DNA recognition, with repeats 2 and 3 making sequence specific DNA contacts and repeat 1 in close proximity with but not directly touching the DNA.9 In Rap1, the principle double-stranded DNA-binding protein found at telomeres of budding yeast,13 two imperfect tandem myb-like repeats make up the DNA-binding domain. Myb repeats in Rap1 are connected by a linker that is somewhat longer than the linker connecting repeats in c-Myb, a feature that may have been adaptive for recognition of telomere DNA repeats that are positioned with variable phasing in the degenerate sequences particular to telomeres of Saccharomyces cerevisiae.5

Figure 2. Myb-like domain and subunit organization.

Figure 2

Myb-like domain and subunit organization. (top panel) c-Myb recognizes its cognate sequence using three imperfect tandem repeats (R1, R2, and R3; pdb id 1mse). Repeats R2 and R3 make direct contact with six basepairs of DNA whilst R1 stabilizes the complex through (more...)

TRF1, the first described human telomere protein,14 binds telomere double-stranded DNA as a dimer,15 with flexible regions connecting the conserved TRF-homology (TRFH) dimerization domain with a single C-terminal DNA-binding myb-like domain.16,17 Taz1 in fission yeast18 and TRF2, a paralog to TRF1 in vertebrates,19,20 share the same TRFH/C-terminal single-myb domain structure seen in TRF1. Consideration of domain architecture in Rap1, Taz1, TRF1 and TRF2 supports the view that telomere double-stranded DNA-binding proteins are constrained to use two myb-like repeats for recognition of telomere DNA. The two myb-like units can be arranged either as tandem repeats as seen in Rap1 or as individual units that are brought together by protein dimerization. Dimerization may have been an adaptive innovation to facilitate telomere-pairing during meiosis in fission yeast21 and looping of telomere DNA as observed for end-protection in vertebrates.22

Single myb-like repeats are found in numerous plant-specific proteins that bind with telomere repeat sequences in vitro.23-26 Members of the plant-specific family defined by TBP1, TRP1 and several TRF-like proteins have a myb-like motif close to the C-terminus and interact with DNA as dimers, features that are similar with those characterizing the Taz1/TRF1/TRF2 family of fission yeast and vertebrates.24-26 These putative telomere proteins have distinguishing plant-specific features, however, in that they lack a recognizable TRFH domain and in each case the myb-like motif is extended to include a fourth helix.26,27 Protein engineering experiments showed that the fourth helix confers in vitro DNA-binding ability to canonical three-helix myb-like domains that otherwise do not bind telomere DNA.26 The fourth helix contributes to a larger hydrophobic core and repositions the DNA-recognition helix slightly but does not appear to enlarge the DNA-interface as inferred from an NMR-determined structure and chemical shift perturbation studies.27 The single myb-like histone-1 (Smh1) protein from maize introduced a second class of myb-like proteins in plants that are implicated in telomere structure on the basis of in vitro DNA-binding.23 Proteins like Smh1 have yet another domain architecture that comprises an N-terminal myb-like domain, a middle domain derived from the conserved globular domain of linker histones and a C-terminal coiled-coil domain.23 High redundancy expected for these plant proteins complicate interpretation of gene knockout and mutant allele expression studies meaning that positive identification of the telomere-specific factors in plants is still in progress. It seems likely, however, that double-stranded DNA-binding factors in plants will add distinct plant-specific domain architectures for this class of telomere proteins.

The OB-Fold

Murzin first described the OB-fold as an example of a homologous protein family for which evidence of common ancestry is preserved in the three-dimensional structures of extant family members but not readily apparent on the basis of amino-acid sequence similarity.28 The X-ray cocrystal structure of a telomere end binding protein (TEBP) from S. nova complexed with telomere single-stranded DNA revealed three OB-folds devoted to recognition of DNA and a fourth OB-fold involved in protein-protein interactions between TEBP-α and TEBPβ proteins.6 These OB-folds placed the otherwise orphaned TEBP-α and TEBPβ proteins in a large family with diverse members that include single-stranded DNA-binding proteins from bacteria,29 replication protein A (RPA),30 and the anti-codon binding domain of many amino-acyl-tRNA synthetases.28,31 Subsequent structure determinations of the single-stranded DNA-binding domains derived from several other telomere binding proteins (Table 1) has led to the conclusion that use of OB-folds is universally conserved among this class of proteins.32-36

OB-folds have been reviewed previously with an emphasis on evolution in host/pathogen contexts,37 recognition of DNA and RNA,31 and superfamily inter-relations inferred from sequence profile-based phylogenetics.38 The OB-fold (Fig. 3) comprises two orthogonally packed anti-parallel beta sheets with s1:s4:s5 strand topology in sheet a and s1':s2:s3 topology in sheet b, with the N-terminal stand s1/s1' continuing as the outer edge of both sheets. Strands s4 and s5 often continue past sheet a and fold over to extend sheet b and thus complete a closed beta-barrel-like structure. The segment joining strands s3 and s4 often includes a short helix, but this region adopts an extended coil-like structure in many counter-examples including an SSB protein from archaea39 and certain OB-folds from RPA.30,40 Most telomere-associated OB-folds are further characterized by a C-terminal alpha-helix but this structural element is neither absolutely conserved among telomere-specific OB-folds nor excluded from nontelomere protein examples. The loops connecting beta strands of the OB-fold are variable in length and these insertions/deletions account for the unreliability of current bioinformatics tools for positively identifying OB-folds.

Figure 3. OB-fold.

Figure 3

OB-fold. (top panel) The second OB-fold from the DNA-binding domain of S. nova TEBP-α in complex with single-stranded telomere DNA (pdb id 2i0q) is shown as a ribbon representation. (bottom panel) Strand topology defining the OB-fold is shown (more...)

The domain and subunit organization of OB-fold telomere components is relevant for understanding inferences regarding molecular evolution. A single OB-fold makes up the DNA-binding domain of Cdc13 from budding yeast.32,41 As far as we currently know from structural biology, the DNA-binding domain of Pot1 from fission yeast contains one OB-fold;34 however, the binding behaviors recently measured for full-length and truncated yeast Pot 1 proteins strongly suggest that there could be two OB-folds involved with DNA binding.42,43 As seen in crystal structures, two OB-folds make up the DNA-binding domain in human Pot133 and the DNA-binding domain of TEBP-α from S. nova.6 In the case of the S. nova telomere complex, an OB-fold contributed by TEBP-β extends the DNA-protein interface so that the complete DNA-binding portion of the α/β hetero-dimer consists of three OB-folds (Fig. 4). The interactions responsible for α/β association are established by means of an extended peptide loop contributed by TEBPβ that wraps around the C-terminal domain of α which comprises an OB-fold as well.6

Figure 4. OB-fold domain and subunit organization.

Figure 4

OB-fold domain and subunit organization. (left-hand panel) OB-folds contained within the human RPA hetero-trimer form a nonsequence specific complex with single-stranded DNA (adapted from multiple structures; pdb ids 1jmc and 1l1o). Subunit RPA-70 contributes the (more...)

Hetero-oligomerization of single-stranded telomere DNA-binding proteins, as first characterized in the S. nova telomere-capping complex,6,44,45 has recently emerged as a theme that is conserved in vertebrates and yeast. Pot1 proteins were identified on the basis of weak but nonetheless significant sequence similarity with the N-terminal OB-fold (αOB-1) of TEBP-α,46 but corresponding homologs for TEBPβ remained elusive until recently. Bioinformatics approaches and structure determination now confirm that the human Pot1-interacting protein Tpp1 (formerly called PTOP, PIP1, or TINT1)47-49 is an OB-fold protein and a homolog of TEBPβ,35,50 suggesting that subunit organization as well as OB-folds are conserved among deeply rooted eukaryotic lineages.

A similar case of hetero-oligomerization involving OB-folds with profound implications for our understanding of telomere protein evolution was recently described for telomere components from budding yeast.51 Cdc13 from S. cerevisiae associates with single-stranded telomere DNA32,52,53 and carries out essential and separable functions for telomere length homeostasis and end-protection by recruiting additional components to telomere ends.54 For end protection, Cdc13 suppresses inappropriate DNA-damage response signals by recruiting Stn155 and Ten1.56 Sequence comparisons, in vitro DNA-binding experiments, yeast two-hybrid tests and complementation by domain swapping in yeast indicate that Stn1 and Ten1 are paralogs of RPA subunits with predicted OB-folds of their own.51 RPA is the eukaryotic single-stranded DNA-binding (SSB) protein with essential functions in semi-conservative DNA replication, recombination and repair.57,58 RPA is a multi-OB-fold protein made up of three different subunits (see Fig. 4).57,58 Sequence similarity, analogous biochemical properties among telomere associated factors and RPA subunits and the ability of an OB-fold derived from Stn1 to functionally replace the OB-fold of an RPA subunit in vivo strongly suggest that a complex consisting of Cdc13, Stn1 and Ten1 constitutes a multi-OB-fold, RPA-like complex dedicated to telomere end protection in budding yeast.51

Origins of Telomere Binding Proteins

Myb-Domain Telomere Proteins Are Derived from Transcription Factors

The ancestral form of the myb-like telomere DNA-binding motif is likely the DNA-binding region of a trans acting factor devoted to regulation of gene expression. Repressors and activators bearing similarity to the myb-motif are widespread among eubacteria, archaea and eukarya indicating that this protein folding unit was well established in the last common ancestor. Transcription factors with multiple myb repeats have experienced explosive expansion especially in animals and plants.59 Rap1, with its two myb-repeat DNA-binding domain, probably represents the descendent of one such protein that aquired a telomeric role even while retaining its gene regulatory functions.60

Ubiquitous use of myb-like domains in the DNA-binding regions of telomere binding proteins suggests a common origin. Domains outside of the DNA-binding region are distinct and different, however and indicate that fixation during the course of evolution involved functions in addition to simply binding telomere sequence repeats. Two added functions apparent in extant proteins are (1) recruitment and coordinated interaction with other telomere factors, some of which have DNA-binding domains of their own and (2) oligomerization of the telomere binding protein through homotypic interactions. Figure 5 shows a phylogenetic tree constructed from amino-acid sequence alignment of homeodomain/myb-like domains from TRF1, TRF2, Taz1, Rap1, as well as TRF-like single-myb proteins from amoeba and plants. In this analysis the TRF1/TRF2 family appears well separated from the single-myb motifs found in other contexts.

Figure 5. Amino-acid sequence alignment and phylogenetic tree constructed for myb-like domains from telomere binding proteins.

Figure 5

Amino-acid sequence alignment and phylogenetic tree constructed for myb-like domains from telomere binding proteins. Residue positions and helix boundaries are those derived from the crystal structure of human TRF2 (pdb id 1w0u). Residues within helix (more...)

The single-myb telomere proteins may have arisen via separate gene duplication events coupled with acquisition of different dimerization domains. The high degree of amino-acid sequence conservation among myb-like motifs argues for a common ancestral protein. It seems also possible, however, that two or more myb motifs derived from different proteins functioning in the binding of T/G-rich gene regulatory sequences would experience similar selective pressures as a role in telomere biology became established. Myb-domains resident in transcription factors may have been predisposed for recruitment to a telomere context since myb-type DNA-binding domains constitute tandem protein repeats suitable for the recognition of tandemly repeated telomere sequences. Convergent evolution following separate gene duplication events and acquisition of accessory domains would account for both the common sequence signature (telobox) of current myb-motifs and the diverse nature of accessory domains involved in dimerization and protein recruitment.

Competition among incipient telomere binding proteins seems to have occurred with generally only one or two closely related proteins retaining the role of direct DNA-binding as is the case for Taz1 in fission yeast,18 TRF1/TRF2 in vertebrates20,61 and Rap1 in budding yeast.62 Rap1 homologs were retained alongside Taz1/TRF lineages of fission yeast and humans,63-66 but these Rap1 homologs lack the positive electrostatic character necessary for DNA-binding67 and currently associate with telomeres via protein-protein interactions.63-66,68 Intriguingly, there is no evidence for converse retention of a TRF-like homolog in budding yeast. Several reports and reviews have noted this puzzling situation and speculate that a telomerase RNA template crisis occurred in the hemiascomycetes leading to TRF loss in this group.63,69

OB-Fold Telomere Proteins Are Derived from SSB

Structural homology first pointed to an evolutionary relationship among OB-fold telomere proteins and RPA,6,30 the eukaryotic SSB devoted to binding single-stranded DNA during DNA replication and repair.57,58 Evidence for such a relationship also comes from studies showing that telomere binding proteins such as TEBP-α and Pot1 have biochemical activities consistent with a role in preventing or resolving folded forms of single-stranded DNA,70-73 a functional role also played by RPA. Additionally, human telomere protein Pot1 activates in vitro unwinding of DNA structures by WRN and BLM helicases74 and together with Tpp1 potentiates telomerase primer-extension reactions,35 properties that are strikingly similar with how RPA potentiates in vitro DNA replication reactions.75,76

SSB proteins constructed with OB-folds and carrying out analogous functions in DNA-replication are ubiquitous among eubacteria and archaea. Subunit organization for bacterial and archaeal SSB proteins is relatively simple with tetramers of a single protein subunit generally found in the SSB proteins of bacteria29 and mitochondria77,78 and a monomeric RPA-like SSB found in Sulfolobus solfataricus.39 A hetero-trimer comprising 70 kDa, 32 kDa and 14 kDa protein subunits is conserved for RPA in yeast and humans.75,79-81 As reviewed above, the three proteins Cdc13, Stn1 and Ten1, each with predicted OB-folds, operate together in budding yeast to suppress inappropriate DNA-damage responses directed at telomeres.51,55,56 The idea emerging is that telomeres are protected by RPA-like complexes, which co-evolved with RPA from an ancestral OB-fold SSB-like protein. Recruitment of an SSB-like protein for chromosome end protection also likely occurred separately for protection of linear chromosomes particular to certain mitochondria.82,83

Reconstruction of the evolutionary history of OB-folds is complicated by rapid divergence among family members. While the myb-like motif is recognizable on the basis of amino-acid sequence similarity, OB-folds are reliably identified only by structure determination. In certain cases, closely related OB-folds retain a degree of sequence similarity; however, even under these circumstances the first OB-fold of the group has been identified from its X-ray or NMR structure. The contrasting pattern of sequence conservation observed for myb-motifs and sequence divergence in the case of OB-fold proteins suggest that strong purifying selection and perhaps convergent evolution have been acting on myb-like domains while comparatively relaxed constraints and divergent evolution operate for the OB-fold proteins.

An amino-acid sequence alignment and phylogenetic tree constructed for OB-folds derived from telomere proteins is shown in Figure 6. In this analysis, equivalent positions were inferred from superposition of three-dimensional structures and amino-acid characters were then treated as if derived from a normal multiple-sequence alignment. Structure-based phylogenetic reconstructions like the one presented here are increasingly being applied in order to examine very deep phylogenies.84 Although most pairwise sequence comparisons have less than 20% sequence identity, the alignment does show one strongly conserved sequence motif [D X (T/S/Y)] in the region connecting strands s2 and s3. Had the sequences been grossly mis-aligned by structural superposition, this motif would not be so consistently represented in the current analysis. Recognized previously as conserved among eukaryotic SSB proteins but absent in bacterial SSB, this motif establishes intra-domain contacts that are incompatible with homo-oligomerization.39 Seeing this [D X (T/S/Y)] motif in telomere binding protein OB-folds, RPA and an archaeal SSB39 provides further support for the idea that telomere proteins co-evolved with RPAs as the archaea and eukarya lineages emerged. The OB-fold phylogenetic tree indicates that partial gene duplications accounting for the multiple OB-folds and subunits characteristic of telomere proteins occurred very early, likely within the last common ancestor of all eukaryotes just as RPA (and RPA-like) complexes were assuming roles in DNA replication.

Figure 6. Alignment and phylogentic tree contructed for OB-folds in single-stranded telomere DNA-binding proteins.

Figure 6

Alignment and phylogentic tree contructed for OB-folds in single-stranded telomere DNA-binding proteins. Secondary structure and residue numbers annotating the alignment were derived from the second OB-fold of TEBP-α, α-OB2. DNA contacts (more...)

The major single-stranded DNA-binding activity associated with the TEBP of S. nova resides in the N-terminal domain of TEBP-α. The second OB-fold from this protein, α-OB2, appears to be a close relative to OB-b, the second OB-fold contained within the major single-stranded DNA-binding domain of RPA-70 (Fig. 6). Extending the TEBP-RPA comparison makes TEBP-α and TEBPβ analogous and perhaps homologous with RPA-70 and RPA-32 subunits. Phosphorylation of protein regions in TEBPβ85,86 and RPA-3287 provides further support for the suggestion that these proteins share a common function and origin. All current evidence indicates that the ciliate TEBP-α/β protein is a hetero-dimer, not a trimer, apparently at odds with descent from an RPA-like complex. The sequence alignment presented in Figure 6 is consistent with loss of a third subunit accomplished through truncation of TEBP-α. Subunit interactions in RPA are established by means of three helices located C-terminal to each of the three OB-folds constituting the RPA trimerization core.40 While TEBPβ makes use of an analogous helix for hetero-dimerization, the C-terminal helix expected to follow the third OB-fold of TEBP-α is missing; the polypeptide chain terminates immediately at the end of strand s5 for this OB-fold (α-OB3 in Fig. 6). Loss of the C-terminal helix and concomitant loss of a third RPA-like subunit may have allowed for more efficient allocation of resources since there are so many telomeres (∼100 million per macronucleus) in this organism,88 each of which is capped by a TEBP-α/β protein complex.

Evolution of Cooperative Telomere Systems

Evolution of telomere proteins appears to have been driven by forces selecting for cooperative systems. Emerging cooperative systems were likely adaptive since these afforded more finely tuned segregation and regulation of two principle telomere functions, telomere homeostasis and telomere end protection. This idea is exemplified by gene duplication apparent for TRF1 and TRF2, which occurred early in the vertebrate lineage (Fig. 5). Gene duplication of the TRF ancestor likely relaxed functional constraints so as to enable specialization and novel biochemical innovations in TRF1 and TRF2. Currently, TRF1 appears most closely associated with telomere length homeostasis whilst TRF2 is essential for sequestering the 3'-terminal DNA and preventing an inappropriate DNA-damage response (reviewed in ref. 2). Fixation of TRF2 may have been driven by its unique ability to condense and supercoil DNA,89 which could facilitate t-loop formation. 22,90 Communication between the emerging TRF1 and TRF2 systems was probably crucial for harmonious co-existence of the paralogs. Duplication of the TRF-encoding gene, therefore, likely imposed strong selective pressure to develop inter-subunit communication as currently mediated by Tpp1 and Ten2 within the cooperative telomere complex shelterin.47,91,92 Similar mechanisms may have driven fixation of duplicated Pot1-encoding genes in Tetrahymena,93 plants94 and rodents.95-97 Although the picture is still coming into focus,98,99 it seems that Pot1 paralogy allows for more specialized telomere functions as is the case for TRF1 and TRF2.

How does protein-protein communication work within complexes of interacting telomere components? Cooperativity was first characterized in the telomere complex from S. nova.44,45,100,101 This telomere system was originally chosen because of natural protein abundance considerations;102-104 however, it still affords unique opportunities to understand protein-protein communication since three-dimensional structures for the entire DNATEBP-αTEBPβ complex6,73 as well as DNA cocomplexes with individual subunits105 and domains106 have been solved. Additionally, protein subunits and domains derived from this system are readily expressed in high yields as required for isothermal titration calorimetry, a method that is revealing the thermodynamic underpinnings for cooperativity and allostery.72,73 These studies show that, despite its apparent simplicity (two proteins plus 16-mer single-stranded DNA), the telomere end complex is remarkably responsive and suggest that allosteric trigger points likely coordinate the hand-off of DNA from a tenacious protective complex to an extension-competent complex with telomerase. Relationships becoming increasingly apparent in telomere systems from protozoa, yeast and humans predict that similar thermodynamic gears and levers have also evolved in the more complicated telomere systems.


This work was supported through a grant from the NIH (R01 GM067994).


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