Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.

中文翻译：

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人类癌症中蛋白质自抑制的广泛改变

自抑制是信号蛋白中普遍存在的变构调节机制。自抑制的减少是某些已知癌症驱动因素的致瘤作用的基础，但自抑制是否在癌症中普遍改变仍然难以捉摸。在这里，我们证明了与癌症相关的错义突变、框内插入/缺失和融合断点在所有癌症类型的抑制性变构开关（IAS）中丰富。选择在癌症中反复突变的 IAS 可以识别已确定的和未知的癌症驱动因素。这些驱动因素的 IAS 中反复出现的错义突变与分子信号传导中独特的癌症特异性变化相关。对于 PPP3CA（钙调神经磷酸酶的催化​​亚基）的具体情况，我们利用生物分子模拟深入了解癌症突变改变自抑制的分子机制，并证明此类突变与与钙调神经磷酸酶信号增强一致的转录组变化相关。我们的综合研究表明，癌细胞积极选择自抑制调节基因改变。