title: Effects of Mutations on the Aggregation Propensity of the Human Prion-Like Protein hnRNPA2B1.
abstract: Hundreds of human proteins contain prion-like domains, which are a subset of low-complexity domains with high amino acid compositional similarity to yeast prion domains. A recently characterized mutation in the prion-like domain of the human heterogeneous nuclear ribonucleoprotein hnRNPA2B1 increases the aggregation propensity of the protein and causes multisystem proteinopathy. The mutant protein forms cytoplasmic inclusions when expressed inDrosophila, the mutation accelerates aggregationin vitro, and the mutant prion-like domain can substitute for a portion of a yeast prion domain in supporting prion activity. To examine the relationship between amino acid sequence and aggregation propensity, we made a diverse set of point mutations in the hnRNPA2B1 prion-like domain. We found that the effects on prion formation inSaccharomyces cerevisiaeand aggregationin vitrocould be predicted entirely based on amino acid composition. However, composition was an imperfect predictor of inclusion formation inDrosophila; while most mutations showed similar behaviors in yeast,in vitro, and inDrosophila, a few showed anomalous behavior. Collectively, these results demonstrate the significant progress that has been made in predicting the effects of mutations on intrinsic aggregation propensity while also highlighting the challenges of predicting the effects of mutations in more complex organisms.
authors.affiliation: Department of Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Kacy R
authors.initials: KR
authors.lastname: Paul
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Amandine
authors.initials: A
authors.lastname: Molliex
authors.affiliation: Department of Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Cascarina
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Boncella
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|HHMI, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado, USA Eric.Ross@ColoState.Edu.
authors.forename: Eric D
authors.identifier: http://orcid.org/0000-0002-6473-9977
authors.initials: ED
authors.lastname: Ross
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009154:Mutation / Q000235:genetics*; D011328:Prions / Q000378:metabolism*; D066329:Protein Aggregates; D000072417:Protein Domains
chemical_list: D000596:Amino Acids; D000682:Amyloid; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D011328:Prions; D066329:Protein Aggregates; C439768:hnRNP A2
keywords: aggregation; low-complexity domain; prion-like; prions