Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

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.

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

“…[4] Although HRs from all amino acids have been reported, the most abundant are hydrophilic, and are characterized by ah igh level of disorder,w hich in many cases precludes crystallization. [2,5,6] As aconsequence,they are underrepresented in the Protein Data Bank (PDB), thus highlighting the need for novel approaches for their structural and dynamic characterization.…”

“…[2] Moreover,p oly-Q expansions form the basis of at least ten neurodegenerative disorders,i ncluding HuntingtonsD isease (HD), Kennedys disease,and several ataxias. [6,7] HD is the most abundant and most well studied poly-Q-related disorder.T he causative agent of this deadly neurodegenerative pathology is the huntingtin protein (htt). [4,7] Although full-length htt has more than 3000 residues,t he first exon (exon1;F igure 1a), which contains the poly-Q tract, is sufficient to replicate much of the pathology in cell and animal models.…”

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

“…Some IDPs contain A and Q homorepeats that tend to form high-order multimers and aggregates associated with 12 and 9 protein misfolding diseases, respectively 80 . A-and Q-rich stretches can also co-occur in the same protein, and occasionally are observed along with QA repeats of variable length, e.g.…”

Site‐Specific Isotopic Labeling (SSIL): Access to High‐Resolution Structural and Dynamic Information in Low‐Complexity Proteins

“…This is especially relevant for af amily of diseases linked to the pathological expansiono fP oly-Q [39,40] andP oly-A [41] tracts, which lead to the formationo fi rreversible aggregates. [42] Structural perturbations exerted by these abnormale xpansions are so far unknown, limiting our understanding of the underlying pathological mechanism and their potential remediation. [43] Low-complexity regionsa nd liquid-liquid phase separation: A large body of examples has identified LCRs inserted in some IDPs as the key elements for the formation of membraneless compartments in cells through aliquid-liquid phase separation (LLPS) mechanism,aphenomenont hat has been shown to be fundamental in am yriad of biological processes.…”

“…The structural features of these homopolymeric regions are largely unknown and possible structure/function relationships remain to be deciphered. This is especially relevant for a family of diseases linked to the pathological expansion of Poly‐Q and Poly‐A tracts, which lead to the formation of irreversible aggregates . Structural perturbations exerted by these abnormal expansions are so far unknown, limiting our understanding of the underlying pathological mechanism and their potential remediation …”