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- W4386807383 abstract "ABSTRACT Identifying pathogenic mutations and predicting their impact on protein structure, function and phenotype remain major challenges in genome sciences. Protein-folding chaperones participate in structure-function relationships by facilitating the folding of protein variants encoded by mutant genes. Here, we utilize a high-throughput protein-protein interaction assay to test HSP70 and HSP90 chaperone interactions as predictors of pathogenicity for variants in the tumor suppressor BRCA1. Chaperones bind 77% of pathogenic BRCA1-BRCT variants, most of which engaged HSP70 more than HSP90. Remarkably, the magnitude of chaperone binding to variants is proportional to the degree of structural and phenotypic defect induced by BRCA1 mutation. Quantitative chaperone interactions identified BRCA1-BRCT separation-of-function variants and hypomorphic alleles missed by pathogenicity prediction algorithms. Furthermore, increased chaperone binding signified greater cancer risk in human BRCA1 carriers. Altogether, our study showcases the utility of chaperones as quantitative cellular biosensors of variant folding and phenotypic severity. HIGHLIGHTS Chaperones detect an abundance of pathogenic folding variants of BRCA1-BRCT. Degree of chaperone binding reflects severity of structural and phenotypic defect. Chaperones identify separation-of-function and hypomorphic variants. Chaperone interactions indicate penetrance and expressivity of BRCA1 alleles." @default.
- W4386807383 created "2023-09-17" @default.
- W4386807383 creator A5015127974 @default.
- W4386807383 creator A5042306685 @default.
- W4386807383 creator A5059745929 @default.
- W4386807383 creator A5067517913 @default.
- W4386807383 creator A5091866180 @default.
- W4386807383 date "2023-09-15" @default.
- W4386807383 modified "2023-10-14" @default.
- W4386807383 title "Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk in BRCA1 Mutation Carriers" @default.
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