Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk in BRCA1 Mutation Carriers.
Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk in BRCA1 Mutation Carriers.
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蛋白质折叠伴侣可预测 BRCA1 突变携带者的结构功能关系和癌症风险。
DOI：
10.1101/2023.09.14.557795
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Karras,GeorgiosIoannis
中科院分区：
文献类型：
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作者：
Gracia,Brant;Montes,Patricia;Gutierrez,AngelicaMaria;Arun,Banu;Karras,GeorgiosIoannis
预测癌症突变的风险对于早期发现和预防至关重要，但人类携带者等位基因严重程度的差异使风险预测混淆。在这里，我们阐明了蛋白质折叠作为驱动肿瘤抑制蛋白brca1突变严重程度差异的细胞机制。通过高通量蛋白-蛋白相互作用分析，我们发现蛋白质折叠伴侣结合模式可以预测BRCA1 c端（BRCT）结构域变异的致病性。HSP70选择性结合94%的致病性BRCA1-BRCT变异，其中大多数与HSP70的结合程度高于HSP90。值得注意的是，HSP70结合的大小与折叠和功能的丧失呈线性相关。我们确定了一类普遍存在的人类半形态BRCA1变异，它们适度地与伴侣结合，并保留部分折叠和功能。此外，伴侣结合在临床上意味着更大的突变外显率和更早的癌症发病。我们的研究结果证明了伴侣作为变异折叠、表型严重程度和癌症风险的定量细胞生物传感器的效用。
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 suppressorBRCA1. 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.