In silico predicted structural and functional insights of all missense mutations on 2B domain of K1/K10 causing genodermatoses
In silico predicted structural and functional insights of all missense mutations on 2B domain of K1/K10 causing genodermatoses
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DOI：
10.18632/oncotarget.10599
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Li, Chen
中科院分区：
文献类型：
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作者：
Banerjee, Santasree;Wu, Qian;Li, Chen
K1和K10相关的遗传性皮肤病的特征是皮肤轻度至重度发红、起泡和肥大的临床症状。在本文中，我们开始计算研究错义突变对K1/K10异源二聚体2B结构域的结构和功能的影响及其在疾病表型中的后果。我们基于人类同源物K5/K14异二聚体的晶体结构对K1/K10异二聚体的结构进行建模，并确定错义突变通过改变物理化学性质、原子间相互作用和残基间原子接触对异二聚体的稳定性和组装能力产生影响。所有错义突变和SNPs之间的比较结构分析表明，取代的氨基酸的位置和物理化学性质与表型变异显着相关。特别是，我们发现的证据表明，一个特定的SNP（K10，第E443 K）是一种致病性nsSNP，破坏形成的疏水核心和不稳定的异源二聚体通过原子间的相互作用的损失。我们的研究是第一个全面的报告，分析位于K1/K10异二聚体卷曲螺旋复合物的2B结构域的突变。
The K1 and K10 associated genodermatoses are characterized by clinical symptoms of mild to severe redness, blistering and hypertrophy of the skin. In this paper, we set out to computationally investigate the structural and functional effects of missense mutations on the 2B domain of K1/K10 heterodimer and its consequences in disease phenotype. We modeled the structure of the K1/K10 heterodimer based on crystal structures for the human homolog K5/K14 heterodimer, and identified that the missense mutations exert their effects on stability and assembly competence of the heterodimer by altering physico-chemical properties, interatomic interactions, and inter-residue atomic contacts. Comparative structural analysis between all the missense mutations and SNPs showed that the location and physico-chemical properties of the substituted amino acid are significantly correlated with phenotypic variations. In particular, we find evidence that a particular SNP (K10, p. E443K) is a pathogenic nsSNP which disrupts formation of the hydrophobic core and destabilizes the heterodimer through the loss of interatomic interactions. Our study is the first comprehensive report analyzing the mutations located on 2B domain of K1/K10 heterodimeric coiled-coil complex.