Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers
Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity of human carriers confound risk predictions. Here, we elucidate protein folding as a cellular mechanism driving differences in mutation severity of tumor suppressor BRCA1. Usin...
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Veröffentlicht in: | Cell reports (Cambridge) 2024-02, Vol.43 (2), p.113803-113803, Article 113803 |
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Zusammenfassung: | Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity of human carriers confound risk predictions. Here, we elucidate protein folding as a cellular mechanism driving differences in mutation severity of tumor suppressor BRCA1. Using a high-throughput protein-protein interaction assay, we show that protein-folding chaperone binding patterns predict the pathogenicity of variants in the BRCA1 C-terminal (BRCT) domain. HSP70 selectively binds 94% of pathogenic BRCA1-BRCT variants, most of which engage HSP70 more than HSP90. Remarkably, the magnitude of HSP70 binding linearly correlates with loss of folding and function. We identify a prevalent class of human hypomorphic BRCA1 variants that bind moderately to chaperones and retain partial folding and function. Furthermore, chaperone binding signifies greater mutation penetrance and earlier cancer onset in the clinic. Our findings demonstrate the utility of chaperones as quantitative cellular biosensors of variant folding, phenotypic severity, and cancer risk.
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•Chaperones detect an abundance of pathogenic folding variants of BRCA1-BRCT•The degree of chaperone binding reflects structural and phenotypic severity•Chaperones identify hypomorphic mutations and contact variants•Chaperone interactions indicate the penetrance and expressivity of BRCA1 alleles
Gracia et al. show that the binding pattern of protein-folding chaperones to BRCA1 variant proteins predicts structure-function relationships and clinical outcomes. They find that the degree of HSP70 binding to variants correlates with age of cancer onset and identify a special class of hypomorphic BRCA1 mutations prevalent within human populations. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2024.113803 |