The importance of the last strand at the C-terminus in βB2-crystallin stability and assembly
The importance of the last strand at the C-terminus in βB2-crystallin stability and assembly
复制标题
C 末端最后一条链在 β B2-晶状体蛋白稳定性和组装中的重要性
DOI：
10.1016/j.bbadis.2013.10.001
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发表时间：
2014-01-01
影响因子：
6.2
通讯作者：
Yan, Yong-Bin
中科院分区：
文献类型：
--
作者：
Zhang, Kai;Zhao, Wei-Jie;Yan, Yong-Bin
先天性白内障是全世界儿童失明的主要原因。研究遗传突变对蛋白质结构和功能的影响，不仅有助于我们了解先天性遗传性白内障的分子机制，而且有助于研究由晶状体特异性基因引起的复杂白内障和非晶状体异常。本研究采用生物物理、细胞动力学和分子动力学相结合的方法，研究了V187M、V187E和R188H突变对sb2晶体蛋白结构和稳定性的影响。V187和R188都位于SB2-crystallin Greek-key motif 4的最后一条链。在体外和细胞水平上，这三种突变都促进了3b2 -晶体蛋白的聚集。这三种突变对3b2 - crystin的影响差异很大：VI 87M影响了c端结构域的疏水核心，VI 87E是希腊键基序的破坏者，破坏了骨干h键网络，而R188H通过解离二聚体和稳定四聚体扰乱了动态寡聚平衡。我们的研究结果强调了最后一条链在s -结晶蛋白的结构完整性、折叠、组装和稳定性中的重要性。更重要的是，我们提出了s -结晶蛋白寡聚物之间动态平衡的扰动是先天性遗传性白内障的重要机制。突变对特定高阶寡聚物的选择性稳定也可能对p-结晶素同聚体和异聚体的稳定性和折叠有害。13个晶体蛋白的长期结构稳定性和功能维持是通过精确调节寡聚平衡来实现的。(C) 2013 Elsevier B.V.版权所有
Congenital cataract is the leading cause of childhood blindness worldwide. Investigations of the effects of inherited mutations on protein structure and function not only help us to understand the molecular mechanisms underlying congenital hereditary cataract, but also facilitate the study of complicated cataract and non-lens abnormities caused by lens-specific genes. In this research, we studied the effects of the V187M, V187E and R188H mutations onSB2-crystallin structure and stability using a combination of biophysical, cellular and molecular dynamic simulation analysis. Both V187 and R188 are located at the last strand of SB2-crystallin Greek-key motif 4. All of the three mutations promoted 3B2-crystallin aggregation in vitro and at the cellular level. These three mutations affected 3B2-crystallin quite differentially: VI 87M influenced the hydrophobic core of the Cterminal domain, VI 87E was a Greek-key motif breaker with the disruption of the backbone H-bonding network, while R188H perturbed the dynamic oligomeric equilibrium by dissociating the dimer and stabilizing the tetramer. Our results highlighted the importance of the last strand in the structural integrity, folding, assembly and stability of S-crystallins. More importantly, we proposed that the perturbation of the dynamic equilibrium betweenS-crystallin oligomers was an important mechanism of congenital hereditary cataract. The selective stabilization of one specific high-order oligomer by mutations might also be deleterious to the stability and folding of the p-crystalllin homomers and heteromers. The long-term structural stability and functional maintenance of13crystallins are achieved by the precisely regulated oligomeric equilibrium. (C) 2013 Elsevier B.V. All rights reserved.