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首页> 外文期刊>Journal of Molecular Biology >Crystal structure of R120G disease mutant of human alphaB-crystallin domain dimer shows closure of a groove.
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Crystal structure of R120G disease mutant of human alphaB-crystallin domain dimer shows closure of a groove.

机译：人αB-晶状蛋白结构域二聚体的R120G疾病突变体的晶体结构显示凹槽闭合。

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摘要

Small heat shock proteins form large cytosolic assemblies from an alpha-crystallin domain conserved arginine in the ACD of several human small heat shock protein family members causes many common inherited diseases of the lens and neuromuscular system. The mutation R120G in alphaB-crystallin causes myopathy, cardiomyopathy and cataract. We have solved the X-ray structure of the excised ACD dimer of human alphaB R120G close to physiological pH and compared it with several recently determined wild-type vertebrate ACD dimer structures. Wild-type excised ACD dimers have a deep groove at the interface floored by a flat extended "bottom sheet." Solid-state NMR studies of large assemblies of full-length alphaB-crystallin have shown that the groove is blocked in the ACD dimer by curvature of the bottom sheet. The crystal structure of R120G ACD dimer also reveals a closed groove, but here the bottom sheet is flat. Loss of Arg120 results in rearrangement of an extensive array of charged interactions across this interface. His83 and Asp80 on movable arches on either side of the interface close the groove by forming two new salt bridges. The residues involved in this extended set of ionic interactions are conserved in Hsp27, Hsp20, alphaA- and alphaB-crystallin sequences. They are not conserved in Hsp22, where mutation of the equivalent of Arg120 causes neuropathy. We speculate that the alphaB R120G mutation disturbs oligomer dynamics, causing the growth of large soluble oligomers that are toxic to cells by blocking essential processes.
机译：小的热激蛋白从几个人类小热激蛋白家族成员的ACD中的α-晶状蛋白结构域保守的精氨酸形成大的胞质组装体，引起晶状体和神经肌肉系统的许多常见遗传疾病。 alphaB-crystallin中的R120G突变会引起肌病，心肌病和白内障。我们已经解决了接近生理pH的人alphaB R120G切除的ACD二聚体的X射线结构，并将其与最近确定的几种野生型脊椎动物ACD二聚体结构进行了比较。野生型切除的ACD二聚体在界面处有一个深沟，该界面由平坦延伸的“底片”铺成地板。对全长αB-晶状蛋白的大型组件的固态NMR研究表明，凹槽被ACD二聚体中的底片曲率阻塞。 R120G ACD二聚体的晶体结构也显示出封闭的凹槽，但此处的底片是平坦的。 Arg120的丢失会导致该界面上大量带电相互作用的重排。界面两侧的可移动拱门上的His83和Asp80通过形成两个新的盐桥来封闭凹槽。在Hsp27，Hsp20，αA-和αB-晶状体蛋白序列中保守了参与这种扩展的离子相互作用的残基。它们在Hsp22中不保守，在Hsp22中，相当于Arg120的突变会引起神经病变。我们推测，alphaB R120G突变扰乱了寡聚物的动力学，导致大的可溶性寡聚物的生长，通过阻止基本过程对细胞有毒。

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