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Abstract
Low complexity regions (LCRs) are very frequent in protein sequences, generally having a lower propensity to form structured domains and tending to be much less evolutionarily conserved than globular domains. Their higher abundance in eukaryotes and in species with more cellular types agrees with a growing number of reports on their function in protein interactions regulated by post-translational modifications. LCRs facilitate the increase of regulatory and network complexity required with the emergence of organisms with more complex tissue distribution and development. Although the low conservation and structural flexibility of LCRs complicate their study, evolutionary studies of proteins across species have been used to evaluate their significance and function. To investigate how to apply this evolutionary approach to the study of LCR function in protein–protein interactions, we performed a detailed analysis for Huntingtin (HTT), a large protein that is a hub for interaction with hundreds of proteins, has a variety of LCRs, and for which partial structural information (in complex with HAP40) is available. We hypothesize that proteins RASA1, SYN2, and KAT2B may compete with HAP40 for their attachment to the core of HTT using similar LCRs. Our results illustrate how evolution might favor the interplay of LCRs with domains, and the possibility of detecting multiple modes of LCR-mediated protein–protein interactions with a large hub such as HTT when enough protein interaction data is available.
Highlights
Huntingtin (HTT) is a large scaffolding protein conserved in Bilateria, including Deuterostomia and Protostomia (e.g., Caenorhabditis elegans), but apparently not in Xenacoelomorpha [1].This protein is ubiquitously expressed in humans [2], a mutation by CAG trinucleotide expansion results in an expanded tract of consecutive glutaminesin the N-terminal region, which causes a pathological effect in the brain resulting in Huntington’s disease, a neurodegenerative disease [3]
As is the case with many structural proteins, HTT contains several low complexity regions (LCRs), which generally correspond to intrinsically disordered regions (IDRs) and could be involved in the modulation of protein interactions regulated by post-translational modifications (PTMs) [4]
Our results suggest that the thresholds used are accurate enough to provide significant insights into low complexity features enriched in HTT interactors
Summary
Huntingtin (HTT) is a large scaffolding protein (with 3142 amino acids in human) conserved in Bilateria, including Deuterostomia (e.g., humans) and Protostomia (e.g., Caenorhabditis elegans), but apparently not in Xenacoelomorpha (the most basal bilaterian clade) [1].This protein is ubiquitously expressed in humans [2], a mutation by CAG trinucleotide expansion results in an expanded tract of consecutive glutamines (polyQ)in the N-terminal region, which causes a pathological effect in the brain resulting in Huntington’s disease, a neurodegenerative disease [3]. Huntingtin (HTT) is a large scaffolding protein (with 3142 amino acids in human) conserved in Bilateria, including Deuterostomia (e.g., humans) and Protostomia (e.g., Caenorhabditis elegans), but apparently not in Xenacoelomorpha (the most basal bilaterian clade) [1] This protein is ubiquitously expressed in humans [2], a mutation by CAG trinucleotide expansion results in an expanded tract of consecutive glutamines (polyQ). As is the case with many structural proteins, HTT contains several low complexity regions (LCRs), which generally correspond to intrinsically disordered regions (IDRs) and could be involved in the modulation of protein interactions regulated by post-translational modifications (PTMs) [4]. Evolutionary approaches to compare LCR usage across selected sets of species have been used to categorize
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