A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics.
A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics.
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DOI：
10.1002/prot.23065
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发表时间：
2011-08
影响因子：
2.9
通讯作者：
Alexov, Emil
中科院分区：
文献类型：
--
作者：
Witham, Shawn;Takano, Kyoko;Schwartz, Charles;Alexov, Emil
关键词：
对X染色体基因的大规模下一代重新测序发现，在一名患有X-连锁智力残疾(XLID)的男性患者中，Xq28上的CLIC2基因存在错义突变，而健康人中没有发现。同时，在健康人的CLIC2基因中发现了大量的nsSNPs(non-synonomous SNP)，表明CLIC2蛋白可以耐受氨基酸替换，并且具有完整的功能。为了测试p.H101Q是致病突变的可能性，我们在电子计算机模拟中计算了p.H101Q突变对CLIC2稳定性、动力学和电离状态的影响，同时比较了可能无害的nsSNPs的影响。研究发现，与其他nsSNPs相比，p.H101Q降低了关节环的灵活性，这对CLIC2的正常功能是重要的；(B)使CLIC2的整体三维结构更稳定，从而减少了CLIC2从可溶性向膜形式移动时预期发生大的构象变化的可能性；以及(C)去除了可能对CLIC2的膜结合重要的带正电荷的残基H101。电子计算机模拟的结果结合多态分析表明，P.H101Q可能是一个致病突变，这是CLIC家族中的第一个突变。
Large-scale next generation resequencing of X chromosome genes identified a missense mutation in the CLIC2 gene on Xq28 in a male with X-linked intellectual disability (XLID) and not found in healthy individuals. At the same time, numerous nsSNPs (nonsynonomous SNP) have been reported in the CLIC2 gene in healthy individuals indicating that the CLIC2 protein can tolerate amino acid substitutions and be fully functional. To test the possibility that p.H101Q is a disease-causing mutation, we performed in silico simulations to calculate the effects of the p.H101Q mutation on CLIC2 stability, dynamics and ionization states while comparing the effects obtained for presumably harmless nsSNPs. It was found that p.H101Q, in contrast with other nsSNPs, (a) lessens the flexibility of the joint loop which is important for the normal function of CLIC2, (b) makes the overall 3D structure of CLIC2 more stable and thus reduces the possibility of the large conformational change expected to occur when CLIC2 moves from a soluble to membrane form and (c) removes the positively charged residue, H101, which may be important for the membrane association of CLIC2. The results of in silico modeling, in conjunction with the polymorphism analysis, suggest that p.H101Q may be a disease-causing mutation, the first one suggested in the CLIC family.
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DOI：
10.1002/prot.10550
发表时间：
2003-01-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Petrey, D;Xiang, ZX;Honig, B
通讯作者：
Honig, B
影响因子：
2.9
作者：
Mi, Wei;Liang, Yu-He;Su, Xiao-Dong
通讯作者：
Su, Xiao-Dong
影响因子：
4.8
作者：
Wu, Hong;Min, Jinrong;Plotnikov, Alexander N.
通讯作者：
Plotnikov, Alexander N.
影响因子：
3
作者：
Song, Yifan;Mao, Junjun;Gunner, M. R.
通讯作者：
Gunner, M. R.
通过冷冻电子显微镜观察 CLIC2-RyR1 相互作用和结构表征。
影响因子：
5.6
作者：
Meng, Xing;Wang, Guoliang;Viero, Cedric;Wang, Qiongling;Mi, Wei;Su, Xiao-Dong;Wagenknecht, Terence;Williams, Alan J.;Liu, Zheng;Yin, Chang-Cheng
通讯作者：
Yin, Chang-Cheng