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

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...

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Autores principales: Schaefer, Martin H., Wanker, Erich E., Andrade-Navarro, Miguel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378862/
https://www.ncbi.nlm.nih.gov/pubmed/22287626
http://dx.doi.org/10.1093/nar/gks011
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author Schaefer, Martin H.
Wanker, Erich E.
Andrade-Navarro, Miguel A.
author_facet Schaefer, Martin H.
Wanker, Erich E.
Andrade-Navarro, Miguel A.
author_sort Schaefer, Martin H.
collection PubMed
description 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.
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spelling pubmed-33788622012-06-20 Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks Schaefer, Martin H. Wanker, Erich E. Andrade-Navarro, Miguel A. Nucleic Acids Res Computational Biology 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. Oxford University Press 2012-05 2012-01-28 /pmc/articles/PMC3378862/ /pubmed/22287626 http://dx.doi.org/10.1093/nar/gks011 Text en © The Author(s) 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Computational Biology
Schaefer, Martin H.
Wanker, Erich E.
Andrade-Navarro, Miguel A.
Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks
title Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks
title_full Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks
title_fullStr Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks
title_full_unstemmed Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks
title_short Evolution and function of CAG/polyglutamine repeats in protein–protein interaction networks
title_sort evolution and function of cag/polyglutamine repeats in protein–protein interaction networks
topic Computational Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378862/
https://www.ncbi.nlm.nih.gov/pubmed/22287626
http://dx.doi.org/10.1093/nar/gks011
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