波谱学杂志Issue(2)：329-341,13.DOI:10.11938/cjmr20150215
以液体核磁共振波谱分析与帕金森氏病相关的I93M突变对人类泛素碳端水解酶结构的影响
Structural Perturbation of the Parkinson’s Disease-Associated I93M Mutation in Human UCH-L1 Revealed by Solution State NMR Spectroscopy
摘要
Abstract
Human ubiquitin C-terminal hydrolase, UCH-L1, is a highly abundant neuronal protein that is implicated in Parkinson’s disease (PD). Familial mutations and post-translational modifications of UCH-L1 have been reported to cause increased aggregation propensity and loss of de-ubiquitination activity, both of which may be pathogenic. We have recently demonstrated that a PD-associated mutation of UCH-L1, namely I93M, significantly destabilizes the folding stability and accelerates the unfolding kinetics (Anderssonet al. J Mol Biol, 2011, 407: 261-272). Here we report the use of solution state NMR spectroscopy, including side-chain methyl chemical shift, backbone relaxation dynamics and residual dipolar coupling (RDC) analyses, to further elucidate how the I93M mutation affects the structure and dynamics of UCH-L1. The results revealed altered side-chain packing within the hydrophobic core around the mutation site. However, such structural perturbation does not affect the fast backbone dynamics on the ns timescale. Furthermore, comparative RDC analysis suggests that the solution structure of UCH-L1 deviates considerably from the reported crystal structure and that the I93M mutation results in long-range structural perturbations far beyond the mutation site. These solution state-based structural findings complement previously reported crystallographic data to provide detailed insights into the impacts of the PD-associated mutation on UCH-L1.关键词
帕金森氏病/人类泛素碳端水解酶/蛋白质折叠/液体核磁共振波谱学/化学位移扰动/有序参数/残余偶极耦合Key words
Parkinson’s disease/UCH-L1/protein folding/solution state NMR spectroscopy/chemical shift perturbation/order parameter/residual dipolar coupling分类
数理科学引用本文复制引用
KUMAR Sriramoju M,呂平江,徐尚德..以液体核磁共振波谱分析与帕金森氏病相关的I93M突变对人类泛素碳端水解酶结构的影响[J].波谱学杂志,2015,(2):329-341,13.基金项目
Grants from “the National Science Council”(100-2113-M-001-031-MY2, and 102-2113-M-001-017-MY2) （100-2113-M-001-031-MY2, and 102-2113-M-001-017-MY2）
