Abduljaleel Zainularifeen, Athar Mohammad, Al-Allaf Faisal A, Al-Dehlawi Saied, Vazquez Jose R
Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O.Box: 715, Makkah 21955, Saudi Arabia.
Science and Technology Unit, Umm Al-Qura University, P.O. Box: 715, Makkah 21955, Saudi Arabia.
Noncoding RNA Res. 2019 Dec 4;4(4):155-173. doi: 10.1016/j.ncrna.2019.11.005. eCollection 2019 Dec.
The human gene codes for a DNA glycosylase involved in the repair of oxidative DNA damage. Faulty MUTYH protein activity causes the accumulation of G→T transversions due to unrepaired 8-G:A mismatches. germ-line mutations in humans are linked with a recessive form of Familial Adenomatous Polyposis (FAP) and colorectal cancer predisposition. We studied the repair capacity of variants identified in MUTYH-associated polyposis (MAP) patients. MAP is inherited in an autosomal recessive type due to mutations in MUTYH (Y165C, G382D, P54S, A22V, Q63R, G45D, S136P and N43S), indicating that both copies of the gene become inactivated. However, the parents of an individual with an autosomal recessive condition may serve as carriers, each harboring one copy of the mutated gene without showing signs or symptoms of MAP. Six protein partners have been associated with MUTYH, four via direct physical interactions, namely hMSH6, hPCNA, hRPA1, and hAPEX1. We examined, for the first time, specific interactions of these protein partners with MAP-associated MUTYH mutants using molecular dynamics simulations. The approach provided tools for exploration of the conformational energy landscape accessible to protein partners. The investigation also determined the impact before and after energy minimization of protein-protein interaction and binding affinities of MUTYH wild type and mutant forms, as well as the interactions with other proteins. Taken together, this study provided new insights into the role of MUTYH and its interacting proteins in MAP.
人类基因编码一种参与氧化DNA损伤修复的DNA糖基化酶。有缺陷的MUTYH蛋白活性会导致由于未修复的8-羟基鸟嘌呤：腺嘌呤错配而积累G→T颠换。人类的种系突变与家族性腺瘤性息肉病（FAP）的隐性形式和结直肠癌易感性有关。我们研究了在MUTYH相关息肉病（MAP）患者中鉴定出的变体的修复能力。MAP以常染色体隐性方式遗传，这是由于MUTYH（Y165C、G382D、P54S、A22V、Q63R、G45D、S136P和N43S）中的突变所致，这表明该基因的两个拷贝均失活。然而，患有常染色体隐性疾病的个体的父母可能是携带者，每个人都携带一个突变基因拷贝，而没有表现出MAP的体征或症状。已经确定有六个蛋白质伴侣与MUTYH相关，其中四个通过直接物理相互作用，即hMSH6、hPCNA、hRPA1和hAPEX1。我们首次使用分子动力学模拟研究了这些蛋白质伴侣与MAP相关的MUTYH突变体的特异性相互作用。该方法为探索蛋白质伴侣可及的构象能量景观提供了工具。该研究还确定了能量最小化前后MUTYH野生型和突变型的蛋白质-蛋白质相互作用和结合亲和力的影响，以及与其他蛋白质的相互作用。综上所述，本研究为MUTYH及其相互作用蛋白在MAP中的作用提供了新的见解。
