Aggregation of polyQ‐extended proteins is promoted by interaction with their natural coiled‐coil partners

Abstract

Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled-coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type-1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin-1 (ATXN1). Here, we suggest that CC partners interacting with the polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC-rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration.

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

“…It is notable that four of these particular suppressors-Sis1, Nup49, Bre5, and Upb3-fit logically into a nuclear trafficking and degradation pathway recently identified in yeast and implicated in Htt103Q toxicity (41,42). In previous literature, most Q-rich proteins that modify Htt toxicity have been shown to be enhancers (7,8,10). Indeed, many of the PrDs we tested that had very strong suppressor activity on their own were not recovered as suppressors in our screen of the fulllength proteins.…”

“…Generally, polyQ-expanded proteins have altered proteinprotein interactions, which either buffer or propagate the deleterious conformational changes of the polyQ-containing protein (6)(7)(8)(9)(10)(11). However, the characteristics that distinguish beneficial from toxic interactions at a molecular level remain enigmatic.…”

Context characterization of amino acid homorepeats using evolution, position, and order

“…They are classified as low complexity regions (LCR), and therefore usually masked by LCR detecting methods. However, although they play important roles in various biological processes, as described for various polyX in certain organisms, they have not been comprehensively characterized yet.…”

A Network of Interdependent Molecular Interactions Describes a Higher Order Nrd1-Nab3 Complex Involved in Yeast Transcription Termination

“…The polyglutamine regions appear to be structurally dynamic, having the ability to adopt many types of secondary structure, including extended conformations, ␣-helices, and ␤-sheets (31). The protein sequence adjacent to polyglutamine stretches also plays a role in conformation because polyglutamine tracts tend to be non-randomly distributed and frequently neighbor helical coiled coil elements (32)(33)(34). Some RNA-binding proteins with low complexity sequences form cytoplasmic foci, such as stress granules that harbor enzymes and substrates of RNA metabolism.…”