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Amino acid homorepeats in proteins

Abstract

Amino acid homorepeats, or homorepeats, are polypeptide segments found in proteins that contain stretches of identical amino acid residues. Although abnormal homorepeat expansions are linked to pathologies such as neurodegenerative diseases, homorepeats are prevalent in eukaryotic proteomes, suggesting that they are important for normal physiology. In this Review, we discuss recent advances in our understanding of the biological functions of homorepeats, which range from facilitating subcellular protein localization to mediating interactions between proteins across diverse cellular pathways. We explore how the functional diversity of homorepeat-containing proteins could be linked to the ability of homorepeats to adopt different structural conformations, an ability influenced by repeat composition, repeat length and the nature of flanking sequences. We conclude by highlighting how an understanding of homorepeats will help us better characterize and develop therapeutics against the human diseases to which they contribute.

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Fig. 1: Functional distribution of homorepeat-containing proteins in yeast and humans.
Fig. 2: Factors influencing the conformation of homorepeats.
Fig. 3: A structural perspective of different types of homorepeats.
Fig. 4: Strategies to target the detrimental effects of homorepeat proteins.

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Acknowledgements

We thank P. L. Chavali, X. Li, A. Hummer and W. Orchard for critically reading the manuscript. This work was supported by the UK Medical Research Council (MC_U105185859; M.M.B., S.C. and B.S.), a European Research Council Consolidator Grant (ERC-COG-2015-682414), a Core grant (S.C.) and Fellowship (A.K.S.) from the Indian Institute of Science Education and Research (IISER) Tirupati. S.C. was supported by the Department of Biotechnology (Ramalingaswami Re-entry Fellowship BT/RLF/Re-entry/05/2018) and the Science and Engineering Research Board (SRG/2019/001785), Government of India. M.M.B. is supported by the American Lebanese Syrian Associated Charities (ALSAC).

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Contributions

S.C. and M.M.B. designed the outline of the manuscript and figures, performed the literature search and wrote the manuscript. B.S. retrieved structural attributes of homorepeats from the Protein Data Bank. S.C. made all the figures. A.K.S. performed the analysis of homorepeat enrichment in the various biological processes and was involved in making figures 1 and 4.

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Correspondence to Sreenivas Chavali or M. Madan Babu.

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Nature Reviews Chemistry thanks P. Bernadó, V. Uversky and S. Michnick for their contribution to the peer review of this work.

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Supplementary information

Glossary

Low-complexity sequence

A sequence with a lower residue diversity than random expectation. Such a sequence tends to contain repeats of a particular residue or is enriched in a few different residues.

Amino acid homorepeat

Or ‘homorepeat’. Protein region consisting of a stretch of identical amino acid residues.

Proteome

The complete set of proteins expressed by a cell or organism.

Genome

The complete genetic material of an organism.

Trinucleotide repeat expansions

Mutations in which repeats of three nucleotides increase in numbers.

Trinucleotide repeat disorders

Genetic disorders arising from abnormal expansion of trinucleotide repeats.

Phenotype

The measurable and observable characteristics of an organism. Determined by the genetic make-up of the organism and the environment.

Protein kinase

An enzyme that post-translationally adds a phosphate group to a Ser, Thr or Tyr residue on its substrate proteins.

Epigenetic

Refers to molecular processes that influence the flow of information between a constant DNA sequence and variable gene-expression patterns; for instance, chemical modification of the DNA or the activity of DNA-associated proteins.

Asymmetric inheritance

Unequal distribution of cellular material between daughter cells after cell division.

Cell cycle

The orchestrated set of events pertaining to the growth and division of a cell.

Genetic variation

Variation in the DNA sequence between different individuals in a population.

Molecular chaperones

Proteins that assist with the folding of other macromolecules in a cell to ensure their proper function.

Synpolydactyly

Limb malformation characterized by fused fingers or toes (syndactyly) and supplementary digits (polydactyly).

Somatic mosaicism

Condition in which cells within a multicellular organism differ genetically because of mutations that arise spontaneously during development or during the lifetime of an individual.

E3 ligase

An enzyme that catalyses the ubiquitylation of substrate proteins. Tripartite motif (TRIM) proteins constitute one of the largest subfamily of E3 ligases involved in the immune response.

Proteasomal degradation

Degradation of ubiquitylated proteins through the cleavage of peptide bonds by the 26S proteasome.

Ubiquitylation

Post-translational enzymatic addition of the ubiquitin protein to diverse substrate proteins.

Autophagosome

A double-membraned vesicle that contains cellular contents destined for autophagy.

Autophagy

A cellular process by which cellular material, such as protein aggregates and damaged organelles, are encapsulated and digested in a cell.

Slipped DNA intermediates

Non-canonical DNA structures that arise during transcription, replication or repair, primarily at repetitive regions.

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Chavali, S., Singh, A.K., Santhanam, B. et al. Amino acid homorepeats in proteins. Nat Rev Chem 4, 420–434 (2020). https://doi.org/10.1038/s41570-020-0204-1

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