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.
Highlights
CC TestEnhancers CC p-Value [20] YFP-ATXN1Q82NT H. sapiens [27]C-terminal ATXN3Q78 D. melanogaster 0.17 [25]N-terminal HTTQ128D. melanogaster 0.17 [26] Q35::YFP C. elegans
We propose that polyQ regions have a significant function that we need to understand, in order to figure out how polyQ expansions result in aggregation and disease
The conservation of polyQ regions and their evolutionary patterns in protein families such as HTT and others suggest that they have an important biological function. Encouraged by this evidence, we recently studied the function of polyQ tracts by association to features in proteins bearing polyQ tracts or interacting with those [13]; the stronger correlations we found were the following: (i) proteins with longer polyQ tracts have a higher number of interactors than proteins with short polyQ tracts or without such sequences and (ii) there is a statistically significant presence of predicted coiled-coil (CC) regions next to polyQ regions
Summary
Polyglutamine (polyQ) diseases are fatal neurological disorders that affect the central nervous system. A characteristic pathological hallmark in polyQ diseases is the formation of large inclusion bodies with insoluble protein aggregates in the nuclei of affected neurons These inclusions consist mainly of polyQ proteins and contain ubiquitin and components of the protein clearance machinery [8]. Our findings are consistent with the previous suggestion that polyQ modulates protein-protein interactions (PPIs) by expanding a neighboring CC upon interaction with a CC from a partner protein (Fig. 1A and B; [15]) Such a CC expansion was observed in X-ray solved structures of the N-terminal fragment of HTT including a helical region, a polyQ and a following polyproline (polyP) domain, fused to the maltosebinding protein [16]. Such hypotheses should be taken into consideration when investigating the effects of interacting proteins on the toxicity of polyQ expanded proteins
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
