Computational analysis of missense mutations causing Snyder-Robinson syndrome.
Computational analysis of missense mutations causing Snyder-Robinson syndrome.
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DOI：
10.1002/humu.21310
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发表时间：
2010-09
期刊：
影响因子：
3.9
通讯作者：
Alexov, Emil
中科院分区：
文献类型：
--
作者：
Zhang, Zhe;Teng, Shaolei;Wang, Liangjiang;Schwartz, Charles E.;Alexov, Emil
Snyder-Robinson综合征是由精胺合酶基因的错义突变引起的，该基因编码529个氨基酸的蛋白质（SMS）。在这里，我们研究，在计算机上，三个错义突变，c.267G>A（p.G56S），c.496T>G（p.V132G）和c.550T>C（p.I150T）在SMS中的分子效应，这些错义突变在临床上被鉴定为引起疾病。单点能量计算，分子动力学模拟和pKa计算揭示了这些突变对SMS的稳定性，灵活性和相互作用的影响。据预测，催化残留物Asp 276应在结合底物之前质子化。pKa计算表明p.I150T突变导致相对于野生型SMS的pKa变化，其涉及与S-甲基-5 '-硫代腺苷（MTA）底物相互作用的可滴定残基。还发现p.I150T错义突变降低C-末端结构域的稳定性，并诱导MTA结合位点附近的结构变化。另外两个错义突变p.G56S和p.V132G远离活性位点，不影响其野生型性质，但影响单体和二聚体的稳定性。具体地，预测p.G56S突变大大降低单体形成二聚体的亲和力，因此应该对SMS功能具有显著影响，因为二聚化对于SMS活性是必需的。
The Snyder-Robinson syndrome is caused by missense mutations in the spermine sythase gene that encodes a protein (SMS) of 529 amino acids. Here we investigate, in silico, the molecular effect of three missense mutations, c.267G>A (p.G56S), c.496T>G (p.V132G) and c.550T>C (p.I150T) in SMS that were clinically identified to cause the disease. Single-point energy calculations, molecular dynamics simulations and pKa calculations revealed the effects of these mutations on SMS's stability, flexibility and interactions. It was predicted that the catalytic residue, Asp276, should be protonated prior binding the substrates. The pKa calculations indicated the p.I150T mutation causes pKa changes with respect to the wild type SMS which involve titratable residues interacting with the S-methyl-5'-thioadenosine (MTA) substrate. The p.I150T missense mutation was also found to decrease the stability of the C-terminal domain and to induce structural changes in the vicinity of the MTA binding site. The other two missense mutations, p.G56S and p.V132G, are away from active site and do not perturb its wild type properties, but affect the stability of both the monomers and the dimer. Specifically, the p.G56S mutation is predicted to greatly reduce the affinity of monomers to form a dimer and therefore should have a dramatic effect on SMS function since dimerization is essential for SMS activity.
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影响因子：
2.9
作者：
Bas, Delphine C.;Rogers, David M.;Jensen, Jan H.
通讯作者：
Jensen, Jan H.
影响因子：
15
作者：
Lau, EY;Bruice, TC
通讯作者：
Bruice, TC
DOI：
10.1107/s0907444906022657
发表时间：
2007-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Kleywegt GJ
通讯作者：
Kleywegt GJ
影响因子：
3.5
作者：
Capon, F;Allen, MH;Trembath, RC
通讯作者：
Trembath, RC
影响因子：
5.7
作者：
Kleywegt, GJ;Henrick, K;van Aalten, DMF
通讯作者：
van Aalten, DMF