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Evolution and function of CAG/polyglutamine repeats in protein-protein interaction networks

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Item Type:Article
Title:Evolution and function of CAG/polyglutamine repeats in protein-protein interaction networks
Creators Name:Schaefer, M.H. and Wanker, E.E. and Andrade-Navarro, M.A.
Abstract:Expanded runs of consecutive trinucleotide CAG repeats encoding polyglutamine (polyQ) stretches are observed in the genes of a large number of patients with different genetic diseases such as Huntington's and several Ataxias. Protein aggregation, which is a key feature of most of these diseases, is thought to be triggered by these expanded polyQ sequences in disease-related proteins. However, polyQ tracts are a normal feature of many human proteins, suggesting that they have an important cellular function. To clarify the potential function of polyQ repeats in biological systems, we systematically analyzed available information stored in sequence and protein interaction databases. By integrating genomic, phylogenetic, protein interaction network and functional information, we obtained evidence that polyQ tracts in proteins stabilize protein interactions. This happens most likely through structural changes whereby the polyQ sequence extends a neighboring coiled-coil region to facilitate its interaction with a coiled-coil region in another protein. Alteration of this important biological function due to polyQ expansion results in gain of abnormal interactions, leading to pathological effects like protein aggregation. Our analyses suggest that research on polyQ proteins should shift focus from expanded polyQ proteins into the characterization of the influence of the wild-type polyQ on protein interactions.
Keywords:Amino Acid Sequence, Human Genome, Molecular Evolution, Molecular Sequence Data, Multiprotein Complexes, Peptides, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Proteins, Sequence Alignment, Trinucleotide Repeats, Animals
Source:Nucleic Acids Research
Publisher:Oxford University Press
Page Range:4273-4287
Date:1 May 2012
Official Publication:https://doi.org/10.1093/nar/gks011
PubMed:View item in PubMed

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