Abstract
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.
Highlights
It is clear that the protein universe includes globular, transmembrane, and fibrous proteins and intrinsically disordered proteins (IDPs) and hybrid proteins with ordered domains and intrinsically disordered protein regions (IDPRs) [1,2]
Being typically involved in regulation, signaling and control pathways, such as those involved in the cell cycle, IDPs/IDPRs are characterized by specific functionality [14,15] that complement the functional repertoire of ordered proteins, which have evolved mainly to carry out efficient catalytic and transport functions
When IDPRs bind to signaling partners, the free energy required to bring about the disorder to order transition takes away from the interfacial, contact free energy, with the net result that a highly specific interaction can be combined with a low net free energy of association [10,36]
Summary
It is clear that the protein universe includes globular, transmembrane, and fibrous proteins and intrinsically disordered proteins (IDPs) and hybrid proteins with ordered domains and intrinsically disordered protein regions (IDPRs) [1,2]. Homorepeat disorders are characterized by the lack of conventional Mendelian transmission and exhibit a phenomenon called anticipation, where the following generation is likely to inherit a longer repeat than the previous one, and this results in increased disease severity with earlier onset [58,59,60]. This is because at the genetic level, the expanded repeats are characterized by meiotic or intergenerational instability and change in size when transmitted from parents to offspring [61]. We represent the results of a systematic analysis of the intrinsic disorder status and the presence of disorder-based functional features (such as sites of posttranslational modifications and disorder-based protein binding sites, known as molecular recognition features, MoRFs) in proteins with pathological repeat expansions
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