人分泌型磷脂酶A2-ⅡA的功能性动力学特征研究  

Study on Functionally Dynamic Features of Human Secretory Phospholipase A2-ⅡA

作　　者：张珊[1] 巩卫康 张娜[1] 李春华[1] ZHANG Shan;GONG Wei-Kang;ZHANG Na;LI Chun-Hua(Faculty of Environmental and Life Sciences,Beijing University of Technology,Beijing 100124,China)

机构地区：[1]北京工业大学环境与生命学部,北京100124

出　　处：《生物化学与生物物理进展》2022年第7期1318-1324,共7页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(31971180,11474013)资助项目。

摘　　要：目的 人分泌型磷脂酶A-ⅡA (secretory phospholipase Agroup ⅡA,sPLA-ⅡA)在调节细胞脂质代谢和信号传导中具有重要作用,参与了多种急、慢性炎症反应。研究其动力学和变构与功能的关系具有重要意义。方法 利用弹性网络模型(elastic network model, ENM)、微扰响应扫描(perturbation-response scanning, PRS)和蛋白质结构网络(protein structure network,PSN)方法对来自人sPLA-ⅡA的31个分子的结构动力学和变构效应进行分析,并探索其动力学共性和特异性与功能的关系。结果 结果表明,对酶的催化和结构稳定起关键作用的催化残基和参与二硫键形成的半胱氨酸残基具有低运动性,这是对酶共有功能的要求;而涉及与钙离子或膜结合的5个结构区域具有高运动性,它们体现了酶成员的特异性。另外,高运动性区域在PRS分析中显示出对外界微扰响应的高敏感性,表明其在变构调节中起重要作用,而低敏感性残基则在维持结构稳定方面发挥了重要作用。残基运动相关性分析发现,人sPLA分子催化位点周围的强相关运动有利于酶催化功能的发挥。结论 本研究有助于深入理解人sPLA-ⅡA成员分子的动力学及功能性变构机制,可为药物设计和准确设计具有精细调节活性的蛋白质提供指导。Objective Human secretory phospholipase Agroup ⅡA(sPLA-ⅡA) plays an important role in the regulation of cellular lipid metabolism and signal transmission, and participates in a variety of acute and chronic inflammatory responses. Investigating the relationship between their dynamics, allostery and functions is of important significance. Methods The elastic network model(ENM), perturbation-response scanning(PRS) and protein structure network(PSN) methods are utilized to analyze the structural dynamics and allostery of 31human s PLA-ⅡA members, and explore the relationship between their shared/specific dynamics and functions.Results The results show that the catalytic residues and cysteine residues involved in disulfide bond formation,important for the enzyme’s catalysis and structural stability respectively, are of minimal mobility, which are the requirements for the enzyme’s shared functions;however, the 5 regions involved in the association with calcium ion/membrane are of high mobility, which embody the specificity of sPLA-ⅡA members. Additionally, the PRS analysis reveals that the above five regions have a high sensitivity to external perturbations, suggesting their important roles in allosteric modulation, while those residues with a low sensitivity play an important role in maintaining structural stability. Finally, the ANM analysis indicates that the strong correlation movements around the catalytic sites of s PLA, are helpful for the enzyme’s catalytic function exertion. Conclusion This study is helpful for the deep understanding of the dynamics and functionally allosteric mechanism of human sPLA-ⅡA,and can provide a guide for drug design and accurate design of proteins with finely tuned activities.

关 键 词：人分泌型磷脂酶A2-ⅡA(sPLA2-ⅡA) 弹性网络模型 微扰响应扫描 结构动力学 变构机制 

分 类 号：Q61[生物学—生物物理学]