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Molecules 2017, 22(12), 2027;

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Department of Molecular Medicine, College of Medicine, Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33612, USA
James A. Haley Veteran’s Hospital, Tampa, FL 33612, USA
Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia
Authors to whom correspondence should be addressed.
Received: 8 November 2017 / Revised: 18 November 2017 / Accepted: 21 November 2017 / Published: 24 November 2017
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Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in non-coding regions of genes typically encoding proteins with ordered structures. Repeats in such non-coding regions of genes can be expressed at the mRNA level. Although they can affect the expression levels of encoded proteins, they are not translated as parts of an affected protein and have no effect on its structure. However, in some cases, the repetitive mRNAs can be translated in a non-canonical manner, generating highly repetitive peptides of different length and amino acid composition. The repeat extension-caused aggregation of a repetitive protein may represent a pivotal step for its transformation into a proteotoxic entity that can lead to pathology. The goals of this article are to systematically analyze molecular mechanisms of the proteinopathies caused by the poly-glutamine and poly-alanine homorepeat expansion, as well as by the polypeptides generated as a result of the microsatellite expansions in non-coding gene regions and to examine the related proteins. We also present results of the analysis of the prevalence and functional roles of intrinsic disorder in proteins associated with pathological repeat expansions. View Full-Text
Keywords: protein repeat expansion; intrinsically disordered protein; intrinsically disordered protein region; homorepeats; protein aggregation; proteinopathies protein repeat expansion; intrinsically disordered protein; intrinsically disordered protein region; homorepeats; protein aggregation; proteinopathies

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Darling, A.L.; Uversky, V.N. Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions. Molecules 2017, 22, 2027.

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