Two TPX2-dependent switches control the activity of Aurora A.

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) simulatio...

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Autores principales:	Xue Xu, Xia Wang, Zhengtao Xiao, Yan Li, Yonghua Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4d7475ab4421490787f7fdfea96a68ab
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spelling	oai:doaj.org-article:4d7475ab4421490787f7fdfea96a68ab2021-11-18T06:59:06ZTwo TPX2-dependent switches control the activity of Aurora A.1932-620310.1371/journal.pone.0016757https://doaj.org/article/4d7475ab4421490787f7fdfea96a68ab2011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21347367/?tool=EBIhttps://doaj.org/toc/1932-6203Aurora 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.Xue XuXia WangZhengtao XiaoYan LiYonghua WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e16757 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xue Xu Xia Wang Zhengtao Xiao Yan Li Yonghua Wang Two TPX2-dependent switches control the activity of Aurora A.
description	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.
format	article
author	Xue Xu Xia Wang Zhengtao Xiao Yan Li Yonghua Wang
author_facet	Xue Xu Xia Wang Zhengtao Xiao Yan Li Yonghua Wang
author_sort	Xue Xu
title	Two TPX2-dependent switches control the activity of Aurora A.
title_short	Two TPX2-dependent switches control the activity of Aurora A.
title_full	Two TPX2-dependent switches control the activity of Aurora A.
title_fullStr	Two TPX2-dependent switches control the activity of Aurora A.
title_full_unstemmed	Two TPX2-dependent switches control the activity of Aurora A.
title_sort	two tpx2-dependent switches control the activity of aurora a.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4d7475ab4421490787f7fdfea96a68ab
work_keys_str_mv	AT xuexu twotpx2dependentswitchescontroltheactivityofauroraa AT xiawang twotpx2dependentswitchescontroltheactivityofauroraa AT zhengtaoxiao twotpx2dependentswitchescontroltheactivityofauroraa AT yanli twotpx2dependentswitchescontroltheactivityofauroraa AT yonghuawang twotpx2dependentswitchescontroltheactivityofauroraa
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Two TPX2-dependent switches control the activity of Aurora A.

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