High-resolution X-ray crystal structures of human γD crystallin (1.25 Å) and the R58H mutant (1.15 Å) associated with aculeiform cataract
High-resolution X-ray crystal structures of human γD crystallin (1.25 Å) and the R58H mutant (1.15 Å) associated with aculeiform cataract
复制标题
DOI：
10.1016/s0022-2836(03)00375-9
复制
发表时间：
2003-05-16
影响因子：
5.6
通讯作者：
Pande, J
中科院分区：
文献类型：
--
作者：
Basak, A;Bateman, O;Pande, J
几种人类白内障与γ晶状体蛋白基因突变有关。其中之一是aculeiform白内障，这是由γ D晶体蛋白中的R58 H突变引起的。我们以前已经表明，这种白内障是由突变蛋白质的结晶引起的，其可溶性比野生型低一个数量级。在这里，我们报告的突变体和野生型蛋白质的非常高分辨率的晶体结构。这两种蛋白质在相同的空间群和晶格中结晶。因此，在两个晶格中的蛋白质-蛋白质和蛋白质-水分子间相互作用的严格比较是可能的。总的来说，突变体和野生型结构之间的差异很小。在位置58处，由于组氨酸和精氨酸在原子水平上的差异，突变体蛋白失去了野生型中存在的直接离子对分子间相互作用;突变体中的相互作用由水分子介导。远离突变位点，突变体和野生型晶格结构在占据交替构象的侧链的身份方面不同。由于在晶体相的相互作用是非常相似的两种蛋白质，我们的结论是，减少的突变体的溶解度主要是由于在溶液相的R58 H突变的影响。这里呈现的结果也很重要，因为它们是人类γ晶体蛋白的第一个高分辨率X射线结构。(C)2003爱思唯尔科技有限公司版权所有。
Several human cataracts have been linked to mutations in the gamma crystallin gene. One of these is the aculeiform cataract, which is caused by an R58H mutation in gammaD crystallin. We have shown previously that this cataract is caused by crystallization of the mutant protein, which is an order of magnitude less soluble than the wild-type. Here, we report the very high-resolution crystal structures of the mutant and wild-type proteins. Both proteins crystallize in the same space group and lattice. Thus, a strict comparison of the protein-protein and protein-water intermolecular interactions in the two crystal lattices is possible. Overall, the differences between the mutant and wild-type structures are small. At position 58, the mutant protein loses the direct ion-pair intermolecular interaction present in the wild-type, due to the differences between histidine and arginine at the atomic level; the interaction in the mutant is mediated by water molecules. Away from the mutation site, the mutant and wild-type lattice structures differ in the identity of side-chains that occupy alternate conformations. Since the interactions in the crystal phase are very similar for the two proteins, we conclude that the reduction in the solubility of the mutant is mainly due to the effect of the R58H mutation in the solution phase. The results presented here are also important as they are the first high-resolution X-ray structures of human gamma crystallins. (C) 2003 Elsevier Science Ltd. All rights reserved.