Graduate School of Sciences and Engineering, Koç University, İstanbul, Turkey.
Department of Chemical Engineering, School of Engineering, Boğaziçi University, İstanbul, Turkey.
Proteins. 2019 Jun;87(6):512-519. doi: 10.1002/prot.25673. Epub 2019 Mar 6.
Missense mutations have various effects on protein structures, also leading to distorted protein dynamics that plausibly affects the function. We hypothesized that missense mutations in cancer-related genes selectively target hinge-neighboring residues that orchestrate collective structural dynamics. To test our hypothesis, we selected 69 cancer-related genes from the Cancer Gene Census database and their representative protein structures from the Protein Data Bank. We first identified the hinge residues in two global modes of motion by applying the Gaussian Network Model. We then showed that missense mutations are significantly enriched on hinge-neighboring residues in oncogenes and tumor suppressor genes. We observed that several oncogenes (eg, MAP2K1, PTPN11, and KRAS) and tumor suppressor genes (eg, EZH2, CDKN2C, and RHOA) strongly exhibit this phenomenon. This study highlights and rationalizes the functional importance of missense mutations on hinge-neighboring residues in cancer.
错义突变对蛋白质结构有多种影响，也导致蛋白质动力学扭曲，可能影响功能。我们假设，癌症相关基因中的错义突变选择性地针对铰链邻近残基，这些残基协调集体结构动力学。为了验证我们的假设，我们从癌症基因普查数据库中选择了 69 个癌症相关基因及其代表的蛋白质结构来自蛋白质数据库。我们首先通过应用高斯网络模型确定了两种全局运动模式中的铰链残基。然后我们表明，错义突变在癌基因和肿瘤抑制基因中的铰链邻近残基上显著富集。我们观察到一些癌基因（例如 MAP2K1、PTPN11 和 KRAS）和肿瘤抑制基因（例如 EZH2、CDKN2C 和 RHOA）强烈表现出这种现象。这项研究突出并合理化了癌症中铰链邻近残基上错义突变的功能重要性。
