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Two TPX2-Dependent Switches Control the Activity of Aurora A
Xu, Xue1; Wang, Xia1; Xiao, Zhengtao1; Li, Yan2,3; Wang, Yonghua1
刊名PLOS ONE
2011-02-09
DOI10.1371/journal.pone.0016757
6期:2
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]AMBER FORCE-FIELD ; DYNAMICS SIMULATION ; MOLECULAR-DYNAMICS ; A ACTIVATION ; KINASE ; PROTEIN ; CANCER ; TPX2 ; CRYSTALLOGRAPHY ; CENTROSOME
英文摘要Aurora A is an important oncogenic kinase for mitotic spindle assembly and a potentially attractive target for human cancers. Its activation could be regulated by ATP cycle and its activator TPX2. To understand the activation mechanism of Aurora A, a series of 20 ns molecular dynamics (MD) simulations were performed on both the wild-type kinase and its mutants. Analyzing the three dynamic trajectories (Aurora A-ATP, Aurora A-ADP, and Aurora A-ADP-TPX2) at the residue level, for the first time we find two TPX2-dependent switches, i.e., switch-1 (Lys-143) and switch-2 (Arg-180), which are tightly associated with Aurora A activation. In the absence of TPX2, Lys-143 exhibits a "closed'' state, and becomes hydrogen-bonded to ADP. Once TPX2 binding occurs, switch-1 is forced to "open'' the binding site, thus pulling ADP away from Aurora A. Without facilitation of TPX2, switch-2 exits in an "open'' conformation which accompanies the outward-flipping movement of P.Thr288 (in an inactive conformation), leading to the crucial phosphothreonine exposed and accessible for deactivation. However, with the binding of TPX2, switch-2 is forced to undergo a "closed'' movement, thus capturing P.Thr288 into a buried position and locking its active conformation. Analysis of two Aurora A (K143A and R180A) mutants for the two switches further verifies their functionality and reliability in controlling Aurora activity. Our systems therefore suggest two switches determining Aurora A activation, which are important for the development of aurora kinase inhibitors.
语种英语
WOS记录号WOS:000287361700032
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被引频次:11[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/142491
专题中国科学院大连化学物理研究所
作者单位1.NW A&F Univ, Ctr Bioinformat, Yangling, Peoples R China
2.Dalian Univ Technol, Sch Chem Engn, Dalian, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
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Xu, Xue,Wang, Xia,Xiao, Zhengtao,et al. Two TPX2-Dependent Switches Control the Activity of Aurora A[J]. PLOS ONE,2011,6(2).
APA Xu, Xue,Wang, Xia,Xiao, Zhengtao,Li, Yan,&Wang, Yonghua.(2011).Two TPX2-Dependent Switches Control the Activity of Aurora A.PLOS ONE,6(2).
MLA Xu, Xue,et al."Two TPX2-Dependent Switches Control the Activity of Aurora A".PLOS ONE 6.2(2011).
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