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Bioessays. Author manuscript; available in PMC Sep 27, 2007.
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PMCID: PMC1994825
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The origins of polypeptide domains

Summary

Three decades ago Gilbert posited that novel proteins arise by re-shuffling genomic sequences encoding polypeptide domains. Today, with numerous genomes and countless genes sequenced, it is well established that recombination of sequences encoding polypeptide domains plays a major role in protein evolution. There is, however, less evidence to suggest how the novel polypeptide domains, themselves, arise. Recent comparisons of genomes from closely related species have revealed numerous species-specific exons, supporting models of domain origin based on “exonization” of intron sequences. Also, a mechanism for the origin of novel polypeptide domains has been proposed based on analyses of insertion-based polymorphisms between orthologous genes across broad phylogenetic spectra and between allelic variants of genes within species. This review discusses these processes and how each might participate in the evolutionary emergence of novel polypeptide domains.

Introduction

One evolutionarily important process is the genesis of novel proteins.(1) Analyses of protein and genome sequences reveal the traces of two predominant mechanisms for creation of novel proteins: (1) gene, genomic region, or genome duplication followed by divergence(2-4) and (2) recombination of sequences encoding portions of existing proteins, such as by exon shuffling.(1,3,59) Gene duplication can produce a second copy of a gene in one generation; however, considerable subsequent mutation and genetic drift may be required before the two resultant genes become functionally distinct. Conversely, recombination can yield a functionally novel protein in a single event.(5,9,10) Recombination can be likened to junkyard creativity, where components salvaged from existing genes are assembled into a new useful product. But how do novel exons or novel polypeptide domains arise in the first place?

Definitions of terms

For this discussion, the term “polypeptide domain” refers to the recognizable evolutionary units or modules from which proteins are composed.(9) Some small proteins may consist of a single polypeptide domain but most proteins comprise multiple domains.(11,12) Importantly, sequences encoding a polypeptide domain can have an evolutionary history and genomic distribution that is distinct from any individual protein in which this domain is found. As modular building blocks, polypeptide domains will frequently also have some degree of structural or functional autonomy.(11,13) The term “oligopeptide” is used here to refer to stretches of amino acids that are too simple to determine whether they are homologous to other similar sequences. Thus, the occurrence of distinct regions of DNA encoding similar oligopeptides could result from either shared ancestry or independent re-emergence. A third more-inclusive term, “motif”, is used to refer to both polypeptide domains and oligopeptides. All instances of the emergence of additional DNA sequences in a gene are referred to here as “insertions”. When repeats of a DNA sequence are found in proximity in a gene, we infer that an ancestral monomer of that sequence templated the more recently inserted copy, and therefore this class of insertions is termed “duplications”.

Genesis of novel polypeptide domains by “exonization” of intronic sequences

Recent comparisons of genomes from closely related species have revealed evolutionarily new exons.(14,15) Most of these are alternative exons that can be optionally included in an mRNA, but the ancestral mRNA lacking this exon can also still be produced (Fig. 1). The implication is that new exons can be assembled over time by accumulation of random mutations within introns of existing genes, that is, by “exonization” of intronic sequences.(15-17)

Figure 1
Genesis of novel polypeptide domains by “exonization” of intron sequences. At top is shown cartoon of a simple gene (exons green, introns uncolored, simplified splice donor and acceptor signals diagramed in blue and red, respectively, ...

Mechanistic evidence of exonization, including evidence for piecemeal assembly of a novel protein-coding region and evidence for acquisition of splicing signals, comes from a study of the multicopy Sdic gene in Drosophila species.(18) Sdic arose very recently by a fusion of representatives of two other multicopy genes, AnnX and Cdic. The recent origin of Sdic and retention of copies of both parental genes allows alignment of both protein-coding and non-coding sequences. The novel first protein-coding exon of Sdic is homologous to intron 3 sequences of the Cdic gene, and arose by an exonization process that included insertion of a 10 bp splice-donor site.(18)

Exonization can also allow assimilation of adjacent intron sequences into an existing exon. Thus, by inactivation of a 5′ splice donor site and activation or acquisition of a downstream site, an exon could be extended into more 3′ sequences. Similarly, by intronic acquisition of 3′ splice acceptor signals, sequences upstream of an existing exon could be assimilated into that exon. An example of the former case was very recently demonstrated for the primate SETMAR gene, in which a 27 bp deletion both eliminated the stop codon for the ancestral SET histone methyl transferase gene and created a 5′ splice donor site. In higher primates, this new splice donor now splices to a novel 3′ acceptor site, resulting in production of a unique mRNA encoding a fusion of SET and the transposase open reading frame of a proximal downstream mariner-family transposon.(19)

Because exonization can rapidly result in novel protein-coding sequences, it has received attention. Theoretically similarly prevalent, but to our knowledge not yet described, might be “intronization”, whereby mutation of splicing signals could lead to rapid deletion of protein-coding sequences from mRNAs. Exon expansion and contraction events such as these may contribute, in part, to the observed evolutionary plasticity of exon-bordering regions.(20)

Are there other origins for polypeptide domains? Insights from TBP

The TATA-binding protein, TBP, is a component of the basal transcription machinery involved in transcription initiation by all three eukaryotic RNA polymerases and by Archaeabacterial RNA pol.(21,22) Accordingly, the 181 amino acid C-terminal core of TBP (TBPCORE) is found in life forms from archaea to mammals; however the N terminus is more variable (Fig. 2). The ~ 120–150 amino acid mammalian TBP N terminus(23) arose at the pre-vertebrate–vertebrate transition, roughly 540 million years ago, and is now found uniquely and universally in vertebrates.(24) Between this N-terminal region and the TBPCORE is a (PXT)n repeat (proline, X, threonine, repeated n times) that is shared among most metazoans, including pre-vertebrate taxa.

Figure 2
Exon- and primary amino acid-structures of vertebrate TBP. At top is depicted the protein-coding exon arrangement of higher vertebrate and cyclostome TBP mRNAs.(27) Heavy lines depict the relevant region of each mRNA, triangles indicate exon–exon ...

Most of the N-terminal domain in mammals lies in a single large exon (exon 3),(25,27) which initially suggested that this domain was “shuffled” onto the TBPCORE of the protein at the pre-vertebrate–vertebrate transition as a single exon.(24) However, further analyses disfavored this model. Besides containing most of the vertebrate-specific region of the protein, exon 3 also encodes the 15 amino acid (PXT)n region, which is shared with pre-vertebrate metazoans, and 8 universally conserved amino acids of the TBP CORE (Fig. 2).(27) Also, a conserved part of the vertebrate-specific N terminus is encoded by exon 2.(26) Thus, two exons would have had to “shuffle” into the tbp locus at the vertebrate transition, the second of which would have had to obtain about 70 nucleotides of novel (PXT)n and TBPCORE amino acid-coding sequence to replace the equivalent sequence in the pre-vertebrate exon. The exon 2/3 and exon 3/4 junctions are in different phases (0 and 2, respectively), which is rare in shuffled exons.(28) Further arguing against exon shuffling, cyclostome vertebrates (lampreys and hagfishes, the most primitive living vertebrates) possess a clade-specific intron (phase 0), splitting the N-terminal protein-coding region into three exons.(24) Lastly, outside of a central glutamine (Q)-repeat sequence, the mammalian TBP N terminus bears no recognizable similarity to any other known genomic sequences in any species, raising the question of what the pre-existing exonic source of these sequences might have been. These subtle complexities in the primary and intron/exon structure of the vertebrate TBP N terminus suggested that the origins of this polypeptide domain were independent of the unit-exon.

Repeat-based mutations in the genome

Natural selection determines the relative reproductive success of individuals. For natural selection to discriminate between individuals in a population, the population must have sufficient genetic diversity to cause fitness differences between individuals. Thus, one should consider what types of genetic differences commonly exist between individuals within a population that might provide a spectrum of potential fitness advantages for niche adaptation. Not surprisingly, the most-common types of genetic variation between individuals are also the types most frequently used in genetic marker analyses. One of these is the number of small repeats at a specific genomic location, in particular repeats of 1–6 nucleotides in length, termed microsatellites.(29) Microsatellite repeat number polymorphisms have been estimated to be up to five orders of magnitude more common than point mutations between individuals;(3) roughly 8% of all microsatellite repeats in the human genome are protein-coding.(31) Thus, at least in some species, repeat-based polymorphisms are likely the greatest source of protein-coding diversity between individuals within a population.

Small sequence repeats can expand or contract in a single generation. For example, the (CAG)n trinucleotide repeat in the Huntingtin gene can expand to severely pathological lengths in a single gamete.(32) Proposed mechanisms involve polymerase slipping during DNA replication and perhaps error-prone repair processes;(33-35) however, the parameters governing the lengths of the repeat units and the frequencies and extents of tandem duplication and deletion of genomic sequences are largely unknown.

Long before the phenotypic consequences of a point mutation can be subjected to natural selection, these errors are screened by replication-associated proofreading activities and generally corrected.(36) Conversely, the extent to which proofreading activities antagonize insertions and deletions of small sequences is unclear.(37,38) In Drosophila melanogaster, a species that generally carries only small numbers of repeats, disruption of the mismatch repair gene Spellchecker1 leads to expansion of repeats, suggesting that a proofreading-like editing mechanism might prevent expansion of small repeats in this species.(39) However, in mammalian cells, disruption of mismatch repair function does not affect the lengths or stabilities of either endogenous or introduced repeats.(40,41) The relative abundance of repeat-based polymorphisms in most species suggests that proofreading activities are at least more permissive of repeat-based errors.

Repeated motifs in proteins

Although perhaps the best-known protein repeats are encoded by microsatellite “trinucleotide repeats”, for example the (CAG)n encoding the Q-repeat in Huntingtin protein,(32,34) repeated motifs are not limited to homo-polymerization of a single amino acid. Common repeat-units vary in length from one to hundreds of amino acids. Familiar examples include Q-, ankyrin-, BZIP-, collagen-, EGF-, immunoglobulin-, WD40-, protease-, protein kinase-, SH-, and fn1-repeats, and others.(10) Moreover, proteins often have semisymmetrical substructures, for example β-barrels, composed of multiple iterations of a common or somewhat diverged motif.

Advanced programs for recognizing repeated protein motifs indicate such repeats are far more common than previously thought. Ponting et al. analyzed 14,226 predicted proteins from D. melanogaster for repeated domains and detected 1,656 that contained at least one substantial internal repeat pair.(42) The repeated domains included 224 novel repeat “groups”, that is a domain in a protein that was shared with at least one other protein, and 455 repeat “orphans”, that is, an internal repeat for which the domain was not found in other proteins.(42) Ponting et al.'s study sought polypeptide repeats that would likely form autonomously structured domains and, therefore, repeats shorter than 30 amino acids were not further studied. Twenty-seven previously unrecognized repeat families were identified; many of these were shared with proteins in other phyla.(42) A more-recent study analyzed over 200,000 proteins in the predicted proteomes of 24 species across all phyla and reported that 13% of these proteins contained repeated domains.(43)

Repeat-based polymorphisms in simple oligopeptides

Polymorphisms in microsatellite-encoded amino acid repeats have traditionally been considered to have little potential as evolutionarily determinant mutations. Excessive expansion of Q-repeats in various otherwise unrelated human proteins results in similar neuropathologies;(34) however, no functional role for Q-repeats in normal proteins has been genetically established and we are aware of no proposal in which Q-repeat expansion would result in a fitness benefit or positive selection. Nevertheless, recent reports indicate that intragenic expansions or contractions of protein-coding repeats are correlated to vertebrate evolution of amelogenin, a protein that participates in tooth development,(44) and to the diverse and rapidly achieved phenotypic differences that have been selected between breeds of domestic dogs.(45) These studies show that small sequence duplications and deletions are frequent events that might commonly modify the activities of existing proteins.(46,47) Importantly, the polymorphisms reported to date are simple microsatellite-based repeats that alter the length of homo-amino acid stretches in their respective proteins. In the case of amelogenin, these subtle modifications likely alter the higher-order assembly of protein/hydroxyapatite complexes that determine the physical characteristics of tooth enamel.(44) In dogs, several polymorphisms have been mapped to regulatory transcription factors—the implication being that these mutations alter downstream gene regulation.(45,46)

Additional evidence that single-generation sequence insertions and deletions might substantially alter protein function comes from analyses on chordate tbp genes. Importantly, some of these studies suggest that these modifications can alter the lengths of both homopolymeric and more complex oligopeptide regions, and that, even in the case of homopolymeric repeats, the causal mechanism can involve duplication/deletion of longer-than-trinucleotide sequence elements. A clinical case report by Shatunov et al. described a patient exhibiting severe neuropathology in which the Q-repeat region of one of the patient's tbp genes had expanded from encoding 37 to encoding 55 consecutive Qs.(48) Subsequent analyses of the patient's relatives indicated that this mutation had occurred de novo in production of one of the gametes that fused to yield the patient. Interestingly, the Q-repeat in the tbp gene, unlike those in many other poly-Q genes, is composed of both Q-encoding codons (CAG and CAA; the Huntingtin poly-Q tract is purely CAG). Although other studies have reported Q-repeat variations in the tbp gene between individuals,(24,49) Shatunov et al. were able to use this codon heterogeneity and familial Q-region sequence determinations to show that expansion of the TBP Q-repeat in this patient did not result from consecutive trinucleotide-expansion steps, but rather, resulted from single-step germline tandem duplication of the 54-base pair sequence CAACAGCAA(CAG)15.(48) Could similar multi-codon duplicative processes also contribute to production of novel complex polypeptide domains?

Evolution of TBP suggests insertion-based genesis of novel complex polypeptide domains

For investigations into the phylogeny of the TBP N terminus (see above), one of us (EES) isolated multiple TBP clones each from amphioxus (Branchiostomata floridae), Pacific hagfish (Eptatretus stoutii), and Atlantic sea lamprey (Petromyzon marinus).(24) Comparisons of clones from multiple individuals of these species revealed interesting polymorphisms that suggested an alternative model for genesis of the N terminus.

Sequences of multiple tbp clones from each of these species revealed almost no intra-species point mutations, synonymous or non-synonymous, protein-coding or non-coding. Conversely, many tbp cDNAs differed by insertions or deletions of small sequence elements. For example, hagfish clones encoded 11, 12, 13, 14 and 15 Q residues in the repeat region.(24) Hagfish also had one more PXT repeat than other vertebrates. However, the greatest insights came from the sequence polymorphisms outside the Q- and (PXT)n-repeat regions in the tbp genes of hagfish and amphioxus.

The hagfish TBP N terminus exhibited insertions of two oligopeptides not found in any other vertebrate, one of 7- and one of 9-amino acids.(24) Amphioxus has a long TBP N terminus that lacks a Q-repeat and cannot be aligned with the vertebrate N terminus. TBP clones from amphioxus differed by insertion of a six nucleotide N-terminal protein-coding element, which was a tandem repeat of adjacent sequences.(24) Moreover, three different isoforms of the 3′-untranslated (UTR) region of amphioxus TBP cDNAs were found; each differed by multiple insertions or deletions of small sequences.(24) In other words, although point mutations, including synonymous mutations, were rare, small sequence insertions and deletions, including some that altered protein-coding, were common.

All insertion-based differences in protein-coding sequences necessarily retained the correct reading frame (multiples of three nucleotides) such that the downstream TBPCORE region would still be translated; however in the 3′ UTR, small sequence insertions and deletions were even more common and were of arbitrary sizes (4, 7, 8, 18, and 23 nucleotides).(24) Thus, unlike point mutations that are constrained by proofreading and natural selection, our data suggested a much more predominant role for natural selection (i.e. maintenance of protein production/function) in constraining insertions and deletions.

Finally, although amino acid alignments show that all vertebrate N termini are homologous through a common ancestor that existed at the pre-vertebrate–vertebrate transition,(24) the inferred progression from this ancestor to higher vertebrates is intriguing. The short complex oligopeptide-encoding insertions in hagfish (see above) are tandem duplications of adjacent sequences (Fig. 2), lending emphasis to the repetitive ancestry of the domain.(24) The hagfish TBP N terminus exhibits a strikingly repetitive character both because it possesses these additional iterations of two repeat units as compared to other vertebrates and because the tandem repeat units are more similar to each other (Fig. 2).(24) Since diverging from an ancestor shared with hagfish, the amino acid substitutions that have accumulated in the lineage leading to higher vertebrates result in the domain in modern tetrapods, outside of the poly-Q region, retaining little evidence of its historical repetitive character.

Based on these observations, it was posited that the TBP N terminus evolved de novo by insertions, deletions and divergence of small sequence elements.(24) At the same time, an equivalent model was proposed as a general mechanism for the evolution of intrinsically unstructured proteins.(50) By this model, one or more small regions within the protein-coding portion of an existing gene could undergo multiple duplications and deletions, eventually resulting in a novel polypeptide sequence that, like the TBP N terminus in primitive vertebrates, (1) would have a repetitive character, and (2) may appear unrelated to the ancestral version. Because a functional protein serves as the starting template, successful modifications should be in sequences that are more permissive of structural alterations, while more constrained domains are conserved. For example, we predict that the complex oligopeptide insertions in the hagfish N terminus (see above) are, on their own, functional subdomains that are at least partially redundant with adjacent copies of the repeat unit (unpublished). As such, their duplication would not alter protein function, but rather, would provide a redundant copy, which could subsequently undergo functional drift while the parental copies of the domain retain the ancestral function.

Nested between the highly polymorphic N terminus-encoding region and the highly polymorphic 3′ UTR region of the tbp locus lie exons encoding one of nature's most-immutable sequences: the TBPCORE.(23) Estimates of purifying selection against amino acid substitutions in the TBPCORE of vertebrates based on rates of non-synonymous to synonymous nucleotide substitutions (dN/dS; loci not under selection should have a dN/dS value of 1.0) indicate this is an extremely highly conserved protein domain (dN/dS = 0.006, for comparison vertebrate histone H2B dN/dS = 0.07). (24) Thus, tbp is not simply a hot locus for accumulation of insertion-based mutations. The close juxtaposition of the highly invariant TBPCORE between two highly polymorphic sequences poses a striking paradox that more likely reflects a focused action of natural selection on the TBCORE than a fickle targeting of mutagenesis to flanking sequences.

Small sequence insertion-based polymorphisms in other proteins

Small insertion-based polymorphisms are common and widely dispersed;(29,30,34) however there are few reports of the insertion of small sequence elements, either by duplication or other means, contributing to the successful genesis of novel polypeptide domains.(24,42,43,50) To determine whether insertion-based modification of functional domains was common, we examined the genes of the major histocompatibility complex (MHC).

MHC genes are multi-gene families in higher vertebrates that participate in adaptive immune defenses. MHC class I (MHC-I) proteins are expressed on the surface of almost all nucleated cells and present proteosome-generated fragments of all proteins being made in a cell, including cancer antigens, viral proteins, or other intracellular pathogen-associated proteins, to circulating cytotoxic Tcells.(51) Each MHC-I protein will preferentially present protein fragments (antigens) with different physical and chemical properties, so diversity in MHC-I genes allows better defense against a broader range of intracellular pathogens.(52,53)

In studying the correlation between pathogen resistance and MHC-I gene diversity in cattle and bison, one of us (CJD) recognized a novel allele of a classical MHC-I molecule (Bibi-N*00501; NCBI accession #DQ989113) in bison that had a direct adjacent seven amino acid sequence duplication in the antigen-binding region of the protein that was not found in other alleles (Fig. 3; Table 1). Further analyses identified the parent allele (Bibi-N*00502; NCBI accession #DQ989114) in the bison population. Alleles Bibi-N*00502 and Bibi-N*00501 are identical except for the 21 nucleotide duplication in Bibi-N*00501. The novel allele is prevalent in the population, suggesting that it is under selective pressure, likely due to its augmenting resistance to an endemic pathogen (unpublished).

Figure 3
Alignment of predicted amino acid sequences of the alpha-2 domain of two bison MHC-I alleles. Allele Bibi-N*00501 is a novel allele with a seven amino acid duplication following position 163 of the parent allele, Bibi-N*00502. Numbering corresponds to ...
Table 1
Small sequence insertions in MHC-I family genes(1)

We searched the more exhaustive collection of mouse MHC-I alleles available in NCBI and found other examples of haplotype diversity arising from small sequence insertions, either as a result of proximal duplication or from some other unidentified source (Table 1). These observations suggest that small insertion-based mutagenesis is an important participant in providing the sequence diversity that pathogens select at MHC-I loci.

Larger duplications

The documentation of expansion of the Q-repeat in a human TBP protein occurring not via multiple consecutive trinucleotide duplications, but rather as a single duplication of a 54 bp sequence(48) (discussed above), demonstrates that sequence duplications are not limited to microsatellite-sized sequences. Thus, it is reasonable to propose that larger semi-symmetrical protein motifs, such as β-barrels, could be born as duplications followed by repeat divergence.

Compelling evidence of duplication and deletion of large and complex protein-coding regions can be inferred from the distribution of one of Ponting et al.'s novel repeats.(42) A duplicated polypeptide domain (repeat unit ~60 amino acids) in the fly Timeless-2 (TIM-2) protein(42) is also found as a duplicated domain in the rat TIM protein. However, the fly TIM protein contains only a monomer of this domain, and the round worm ortholog of TIM-2 contains three diverged tandem iterations of the domain.(42) The difference in numbers of diverged repeat units within this family of proteins indicate that the mechanisms of altering the numbers of repeats in TIM proteins must occur at a greater frequency than the gene duplicative mechanisms that led to the paralogous gene family.

Bjorklund et al. addressed the possibility that intrageneic domain repeats might arise by exon shuffling.(43) Their analysis of over 5,000 domain repeat families across all phyla indicated that, only in the case of a few extracellular repeat domains in higher eukaryotes, most notably the immunoglobulin- and EGF-repeat families, is the intron/exon structure expected to be compatible with an exon shuffling-based mechanism for repeat expansion.(43) Thus, even in the case of large or complex polypeptide domains, like the TIM domain discussed above,(42) a likely mechanism of altering their numbers within a gene would be by single-step tandem duplications of the repeat unit in the germ-line.

Conclusions

Recent studies provide support for the decades-old prediction that novel polypeptide domains can arise by exonization of intron sequences.(6) The abundance of novel exons not shared between closely related species suggests that this is a common source of unique protein-coding sequence.(14,15)

Studies on simple and complex oligopeptide insertions and deletions in proteins reveal an alternative means of creating a novel polypeptide domain within an existing protein-coding sequence. Perhaps the most-abundant type of genetic variability, both protein-coding and non-coding, between individuals within populations results from insertions and deletions of small sequence elements.(30) The lengths of protein-coding tri-nucleotide repeat regions have long been known to differ between individuals, occasionally with pathological consequences. Recently, species-specific differences in tooth structure and physiological differences between dog breeds have been correlated to alterations in the lengths of homo-amino acid repeats in specific proteins.(44,45) This suggests that, besides being either neutral or deleterious, some modifications of small repeat elements can result in positive (Darwinian) selection.(46,47)

Analysis of one pathological incident of a Q-repeat expansion in a human family showed that homo-amino acid repeat expansion can occur by single-step duplications of complex larger-than-trinucleotide sequences.(48) The same mechanism might duplicate other complex nucleic acid sequences. Repetitive substructures are common in proteins, suggesting that sequences encoding the compositional motifs might be re-used repeatedly in the genesis of a protein. These observations lend insights into understanding the origins of more complex repetitive domains and substructures in proteins. They also suggest that this is a highly active process that has the potential to rapidly and drastically alter protein-coding sequences within existing genes, resulting in the appearance of entirely novel polypeptide domains.

Acknowledgments

The authors thank O. Lucas, J. Langeland, Y.-s. Piao, A. Bondareva, and J. Prigge for their comments on the manuscript. We thank Drs. Hong Li and Donald L. Traul for permission to include data from the USDA, Animal Disease Research Unit, Bison Malignant Catarrhal Fever Research project (USDA, ARS grant #CWU-5348-32000-018-00D).

Funding agency: E.E.S. was supported by a new investigator award (#5-FY00-520) and a research grant (#6-FY03-61) from the March of Dimes Foundation, a career development award (#0446536) and a research grant (#0090884) from the National Science Foundation, and a research grant (#1R01-AI55739) from the National Institutes of Health. C.J.D. was supported by the Washington State University, Safe Food Initiative and USDA Animal Health Formula Funds.

Abbreviations

bp
base pairs
C
carboxyl
EGF
epidermal growth factor
MHC
major histocompatibility complex
MHC-I
MHC Class l
N
amino
Q
glutamine
RNA pol
RNA polymerase
TBP
TATA-binding protein
TBPCORE
the widely conserved 181 amino acid TBP C-terminal region
TIM
Timeless protein
UTR
untranslated region

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