Protein tandem repeats

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Common examples of protein tandem repeat structures: the WD40 repeat domain of beta-TrCP (green), leucine-rich repeat domain of TLR2 (red), armadillo repeat domain of beta-catenin (blue), ankyrin repeat domain of ANKRA2 (orange), kelch repeat domain of Keap1 (yellow) and HEAT repeat domain of a PP2A regulatory subunit R1a (magenta). Solenoid-domain-examples.png
Common examples of protein tandem repeat structures: the WD40 repeat domain of beta-TrCP (green), leucine-rich repeat domain of TLR2 (red), armadillo repeat domain of beta-catenin (blue), ankyrin repeat domain of ANKRA2 (orange), kelch repeat domain of Keap1 (yellow) and HEAT repeat domain of a PP2A regulatory subunit R1a (magenta).

An array of protein tandem repeats is defined as several (at least two) adjacent copies having the same or similar sequence motifs. These periodic sequences are generated by internal duplications in both coding and non-coding genomic sequences. Repetitive units of protein tandem repeats are considerably diverse, ranging from the repetition of a single amino acid to domains of 100 or more residues. [1] [2]

Contents

Schematic representation of tandem repeat sequence. Protein tandem repeat.png
Schematic representation of tandem repeat sequence.

"Repeats" in proteins

Example multiple sequence alignment of a pentapeptide repeat leading to a tandem repeat structure PRP align.jpg
Example multiple sequence alignment of a pentapeptide repeat leading to a tandem repeat structure

In proteins, a "repeat" is any sequence block that returns more than one time in the sequence, either in an identical or a highly similar form. The degree of similarity can be highly variable, with some repeats maintaining only a few conserved amino acid positions and a characteristic length. Highly degenerate repeats can be very difficult to detect from sequence alone. Structural similarity can help to identify repetitive patterns in sequence.

Structure

Repetitiveness does not in itself indicate anything about the structure of the protein. As a "rule of thumb", short repetitive sequences (e.g. those below the length of 10 amino acids) may be intrinsically disordered, and not part of any folded protein domains. Repeats that are at least 30 to 40 amino acids long are far more likely to be folded as part of a domain. Such long repeats are frequently indicative of the presence of a solenoid domain in the protein.

Approximately half of the tandem repeat regions have intrinsically disordered conformation being naturally unfolded. [3] [4] [5] Examples of disordered repetitive sequences include the 7-mer peptide repeats found in the RPB1 subunit of RNA polymerase II, [6] or the tandem beta-catenin or axin binding linear motifs in APC (adenomatous polyposis coli). [7] The other half of the regions with the stable 3D structure has a plethora of shapes and functions. [8] [9] Examples of short repeats exhibiting ordered structures include the three-residue collagen repeat or the five-residue pentapeptide repeat that forms a beta helix structure.

Classification

Depending on the length of the repetitive units, their protein structures can be subdivided into five classes: [8] [9]

  1. crystalline aggregates formed by regions with 1 or 2 residue long repeats, archetypical low complexity regions
  2. fibrous structures stabilized by inter-chain interactions with 3-7 residue repeats
  3. elongated structures with repeats of 5–40 residues dominated by solenoid proteins
  4. closed (not elongated) structures with repeats of 30-60 residues as toroid repeats
  5. beads on a string structures with typical size of repeats over 50 residues, which are already large enough to fold independently into stable domains.

Function

Some well-known examples of proteins with tandem repeats are collagen, which plays a key role in the arrangement of the extracellular matrix; alpha-helical coiled coils having structural and oligomerization functions; leucine-rich repeat proteins, which specifically bind some globular proteins by their concave surfaces; and zinc-finger proteins, which regulate the expression of genes by binding DNA.

Tandem repeat proteins frequently function as protein-protein interaction modules. The WD40 repeat is a prime example of this function. [10]

Distribution in proteomes

Tandem repeats are ubiquitous in proteomes and occur in at least 14% of all proteins. [11] For example, they are present in almost every third human protein and even in every second protein from Plasmodium falciparum or Dictyostelium discoideum. [11] [12] Tandem repeats with short repetitive units (especially homorepeats) are more frequent than others. [11]

Annotation methods

Protein tandem repeats can be either detected from sequence or annotated from structure. Specialized methods were built for the identification of repeat proteins. [13]

Sequence-based strategies, based on homology search [14] or domain assignment, [15] [16] mostly underestimate TRs due to the presence of highly degenerate repeat units. [17] A recent study to understand and improve Pfam coverage of the human proteome [17] showed that five of the ten largest sequence clusters not annotated with Pfam are repeat regions. Alternatively, methods requiring no prior knowledge for the detection of repeated substrings can be based on self-comparison, [18] [19] clustering [20] [21] or hidden Markov models. [22] [23] Some others rely on complexity measurements [13] or take advantage of meta searches to combine outputs from different sources. [24] [25]

Structure-based methods instead take advantage of the modularity of available PDB structures to recognize repetitive elements. [26] [27] [28] [29] [30]

Related Research Articles

<span class="mw-page-title-main">Sequence alignment</span> Process in bioinformatics that identifies equivalent sites within molecular sequences

In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Aligned sequences of nucleotide or amino acid residues are typically represented as rows within a matrix. Gaps are inserted between the residues so that identical or similar characters are aligned in successive columns. Sequence alignments are also used for non-biological sequences, such as calculating the distance cost between strings in a natural language or in financial data.

In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an N-glycosylation site motif can be defined as Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro residue.

In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have to be associated with a sequence motif; it can be represented by different and completely unrelated sequences in different proteins or RNA.

<span class="mw-page-title-main">Structural alignment</span> Aligning molecular sequences using sequence and structural information

Structural alignment attempts to establish homology between two or more polymer structures based on their shape and three-dimensional conformation. This process is usually applied to protein tertiary structures but can also be used for large RNA molecules. In contrast to simple structural superposition, where at least some equivalent residues of the two structures are known, structural alignment requires no a priori knowledge of equivalent positions. Structural alignment is a valuable tool for the comparison of proteins with low sequence similarity, where evolutionary relationships between proteins cannot be easily detected by standard sequence alignment techniques. Structural alignment can therefore be used to imply evolutionary relationships between proteins that share very little common sequence. However, caution should be used in using the results as evidence for shared evolutionary ancestry because of the possible confounding effects of convergent evolution by which multiple unrelated amino acid sequences converge on a common tertiary structure.

BioJava is an open-source software project dedicated to provide Java tools to process biological data. BioJava is a set of library functions written in the programming language Java for manipulating sequences, protein structures, file parsers, Common Object Request Broker Architecture (CORBA) interoperability, Distributed Annotation System (DAS), access to AceDB, dynamic programming, and simple statistical routines. BioJava supports a huge range of data, starting from DNA and protein sequences to the level of 3D protein structures. The BioJava libraries are useful for automating many daily and mundane bioinformatics tasks such as to parsing a Protein Data Bank (PDB) file, interacting with Jmol and many more. This application programming interface (API) provides various file parsers, data models and algorithms to facilitate working with the standard data formats and enables rapid application development and analysis.

<span class="mw-page-title-main">Pfam</span> Database of protein families

Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The most recent version, Pfam 35.0, was released in November 2021 and contains 19,632 families.

InterPro is a database of protein families, protein domains and functional sites in which identifiable features found in known proteins can be applied to new protein sequences in order to functionally characterise them.

Rfam is a database containing information about non-coding RNA (ncRNA) families and other structured RNA elements. It is an annotated, open access database originally developed at the Wellcome Trust Sanger Institute in collaboration with Janelia Farm, and currently hosted at the European Bioinformatics Institute. Rfam is designed to be similar to the Pfam database for annotating protein families.

<span class="mw-page-title-main">Protein domain</span> Self-stable region of a proteins chain that folds independently from the rest

In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of several domains, and a domain may appear in a variety of different proteins. Molecular evolution uses domains as building blocks and these may be recombined in different arrangements to create proteins with different functions. In general, domains vary in length from between about 50 amino acids up to 250 amino acids in length. The shortest domains, such as zinc fingers, are stabilized by metal ions or disulfide bridges. Domains often form functional units, such as the calcium-binding EF hand domain of calmodulin. Because they are independently stable, domains can be "swapped" by genetic engineering between one protein and another to make chimeric proteins.

<span class="mw-page-title-main">Transcription activator-like effector</span>

TALeffectors are proteins secreted by some β- and γ-proteobacteria. Most of these are Xanthomonads. Plant pathogenic Xanthomonas bacteria are especially known for TALEs, produced via their type III secretion system. These proteins can bind promoter sequences in the host plant and activate the expression of plant genes that aid bacterial infection. The TALE domain responsible for binding to DNA is known to have 1.5 to 33.5 short sequences that are repeated multiple times. Each of these repeats was found to be specific for a certain base pair of the DNA. These repeats also have repeat variable residues (RVD) that can detect specific DNA base pairs. They recognize plant DNA sequences through a central repeat domain consisting of a variable number of ~34 amino acid repeats. There appears to be a one-to-one correspondence between the identity of two critical amino acids in each repeat and each DNA base in the target sequence. These proteins are interesting to researchers both for their role in disease of important crop species and the relative ease of retargeting them to bind new DNA sequences. Similar proteins can be found in the pathogenic bacterium Ralstonia solanacearum and Burkholderia rhizoxinica, as well as yet unidentified marine microorganisms. The term TALE-likes is used to refer to the putative protein family encompassing the TALEs and these related proteins.

A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred. Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident. Sequence homology can then be deduced even if not apparent. Superfamilies typically contain several protein families which show sequence similarity within each family. The term protein clan is commonly used for protease and glycosyl hydrolases superfamilies based on the MEROPS and CAZy classification systems.

C6orf222 is a protein that in humans is encoded by the C6orf222 gene (6p21.31). C6orf222 is conserved in mammals, birds and reptiles with the most distant ortholog being the green sea turtle, Chelonia mydas. The C6orf222 protein contains one mammalian conserved domain: DUF3293. The protein is also predicted to contain a BH3 domain, which has predicted conservation in distant orthologs from the clade Aves.

<span class="mw-page-title-main">SHLD1</span> Protein-coding gene in the species Homo sapiens

SHLD1 or shieldin complex subunit 1 is a gene on chromosome 20. The C20orf196 gene encodes an mRNA that is 1,763 base pairs long, and a protein that is 205 amino acids long.

<span class="mw-page-title-main">C2orf16</span> Protein-coding gene in the species Homo sapiens

C2orf16 is a protein that in humans is encoded by the C2orf16 gene. Isoform 2 of this protein is 1,984 amino acids long. The gene contains 1 exon and is located at 2p23.3. Aliases for C2orf16 include Open Reading Frame 16 on Chromosome 2 and P-S-E-R-S-H-H-S Repeats Containing Sequence.

Low complexity regions (LCRs) in protein sequences, also defined in some contexts as compositionally biased regions (CBRs), are regions in protein sequences that differ from the composition and complexity of most proteins that is normally associated with globular structure. LCRs have different properties from normal regions regarding structure, function and evolution.

<span class="mw-page-title-main">Toroid repeat proteins</span>

A toroid repeat is a protein fold composed of repeating subunits, arranged in circular fashion to form a closed structure.

<span class="mw-page-title-main">Backbone-dependent rotamer library</span> Collection of data on conformations of a given proteins amino acid side chains

In biochemistry, a backbone-dependent rotamer library provides the frequencies, mean dihedral angles, and standard deviations of the discrete conformations of the amino acid side chains in proteins as a function of the backbone dihedral angles φ and ψ of the Ramachandran map. By contrast, backbone-independent rotamer libraries express the frequencies and mean dihedral angles for all side chains in proteins, regardless of the backbone conformation of each residue type. Backbone-dependent rotamer libraries have been shown to have significant advantages over backbone-independent rotamer libraries, principally when used as an energy term, by speeding up search times of side-chain packing algorithms used in protein structure prediction and protein design.

Computational methods that use protein sequence and/ or protein structure to predict protein aggregation. The table below, shows the main features of software for prediction of protein aggregation

References

  1. ↑ Heringa J (June 1998). "Detection of internal repeats: how common are they?". Current Opinion in Structural Biology. 8 (3): 338–45. doi:10.1016/s0959-440x(98)80068-7. PMID   9666330.
  2. ↑ Andrade MA, Ponting CP, Gibson TJ, Bork P (May 2000). "Homology-based method for identification of protein repeats using statistical significance estimates". Journal of Molecular Biology. 298 (3): 521–37. doi:10.1006/jmbi.2000.3684. PMID   10772867.
  3. ↑ Tompa P (September 2003). "Intrinsically unstructured proteins evolve by repeat expansion". BioEssays. 25 (9): 847–55. doi:10.1002/bies.10324. PMID   12938174. S2CID   32684524.
  4. ↑ Simon M, Hancock JM (2009). "Tandem and cryptic amino acid repeats accumulate in disordered regions of proteins". Genome Biology. 10 (6): R59. doi: 10.1186/gb-2009-10-6-r59 . PMC   2718493 . PMID   19486509.
  5. ↑ Jorda J, Xue B, Uversky VN, Kajava AV (June 2010). "Protein tandem repeats - the more perfect, the less structured" (PDF). The FEBS Journal. 277 (12): 2673–82. doi:10.1111/j.1742-4658.2010.07684.x. PMC   2928880 . PMID   20553501.
  6. ↑ Meyer PA, Ye P, Zhang M, Suh MH, Fu J (June 2006). "Phasing RNA polymerase II using intrinsically bound Zn atoms: an updated structural model". Structure. 14 (6): 973–82. doi: 10.1016/j.str.2006.04.003 . PMID   16765890.
  7. ↑ Liu J, Xing Y, Hinds TR, Zheng J, Xu W (June 2006). "The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin". J. Mol. Biol. 360 (1): 133–44. doi:10.1016/j.jmb.2006.04.064. PMID   16753179.
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  13. 1 2 Pellegrini M, Renda ME, Vecchio A (2012). "Ab initio detection of fuzzy amino acid tandem repeats in protein sequences". BMC Bioinformatics. 13 (Suppl 3): S8. doi: 10.1186/1471-2105-13-S3-S8 . PMC   3402919 . PMID   22536906.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ↑ Andrade MA, Ponting CP, Gibson TJ, Bork P (2000). "Homology-based method for identification of protein repeats using statistical significance estimates". J Mol Biol. 298 (3): 521–37. doi:10.1006/jmbi.2000.3684. PMID   10772867.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ El-Gebali S, Mistry J, Bateman A, Eddy SR, Luciani A, Potter SC; et al. (2019). "The Pfam protein families database in 2019". Nucleic Acids Res. 47 (D1): D427–D432. doi:10.1093/nar/gky995. PMC   6324024 . PMID   30357350.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  19. ↑ Szklarczyk R, Heringa J (2004). "Tracking repeats using significance and transitivity". Bioinformatics. 20 (Suppl 1): i311-7. doi: 10.1093/bioinformatics/bth911 . PMID   15262814.
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  25. ↑ Schaper E, Anisimova M (2015). "The evolution and function of protein tandem repeats in plants". New Phytol. 206 (1): 397–410. doi: 10.1111/nph.13184 . PMID   25420631. S2CID   20656455.
  26. ↑ Abraham AL, Rocha EP, Pothier J (2008). "Swelfe: a detector of internal repeats in sequences and structures". Bioinformatics. 24 (13): 1536–7. doi:10.1093/bioinformatics/btn234. PMC   2718673 . PMID   18487242.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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