Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity.
Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity.
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DOI：
10.1016/j.molcel.2013.11.013
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发表时间：
2014-01-09
期刊：
影响因子：
16
通讯作者：
Turk, Benjamin E.
中科院分区：
文献类型：
--
作者：
Chen, Catherine;Ha, Byung Hak;Thevenin, Anastasia F.;Lou, Hua Jane;Zhang, Rong;Yip, Kevin Y.;Peterson, Jeffrey R.;Gerstein, Mark;Kim, Philip M.;Filippakopoulos, Panagis;Knapp, Stefan;Boggon, Titus J.;Turk, Benjamin E.
真核蛋白激酶一般分为酪氨酸特异性或丝氨酸-苏氨酸特异性。虽然从它们的初级序列检查中不明显，但许多丝氨酸-苏氨酸激酶表现出对丝氨酸或苏氨酸作为磷受体残基的显著偏好。在这里，我们展示了位于激酶激活段的残基，我们称之为“DFG+1”残基，作为丝氨酸-苏氨酸磷酸化位点特异性的主要决定因素。该残基的突变足以改变多种激酶的磷酸化位点偏好，包括丝氨酸特异性激酶PAK4和苏氨酸特异性激酶MST4。肽底物磷酸化的动力学分析和pak4肽复合物的晶体结构表明，磷酸化受体残基的偏好并不是由受青睐的底物更强的结合所介导的。相反，有利的激酶-磷受体组合可能促进最适合催化的构象。了解控制激酶磷酸化受体偏好的规则允许激酶根据其序列被分类为丝氨酸或苏氨酸特异性。一个单一的活性位点残基可以决定激酶磷酸化受体的特异性，有利和不利的底物促进不同的激酶结合构象，一个简单的规则预测激酶磷酸化受体的偏好从它的DFG+1残基
Eukaryotic protein kinases are generally classified as being either tyrosine or serine-threonine specific. Though not evident from inspection of their primary sequences, many serine-threonine kinases display a significant preference for serine or threonine as the phosphoacceptor residue. Here we show that a residue located in the kinase activation segment, which we term the “DFG+1” residue, acts as a major determinant for serine-threonine phosphorylation site specificity. Mutation of this residue was sufficient to switch the phosphorylation site preference for multiple kinases, including the serine-specific kinase PAK4 and the threonine-specific kinase MST4. Kinetic analysis of peptide substrate phosphorylation and crystal structures of PAK4-peptide complexes suggested that phosphoacceptor residue preference is not mediated by stronger binding of the favored substrate. Rather, favored kinase-phosphoacceptor combinations likely promote a conformation optimal for catalysis. Understanding the rules governing kinase phosphoacceptor preference allows kinases to be classified as serine or threonine specific based on their sequence. A single active site residue can determine kinase phosphoacceptor specificity Favored and disfavored substrates promote distinct kinase-bound conformations A simple rule predicts kinase phosphoacceptor preference from its DFG+1 residue
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影响因子：
5.7
作者：
Eswaran, Jeyanthy;Lee, Wen Hwa;Debreczeni, Judit E.;Filippakopoulos, Panagis;Turnbull, Andrew;Fedorov, Oleg;Deacon, Sean W.;Peterson, Jeffrey R.;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
14.9
作者：
Hornbeck PV;Kornhauser JM;Tkachev S;Zhang B;Skrzypek E;Murray B;Latham V;Sullivan M
通讯作者：
Sullivan M
影响因子：
11.4
作者：
Hubbard, SR
通讯作者：
Hubbard, SR
DOI：
10.1126/science.1236566
发表时间：
2013-07-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kang SA;Pacold ME;Cervantes CL;Lim D;Lou HJ;Ottina K;Gray NS;Turk BE;Yaffe MB;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1073/pnas.1214447109
发表时间：
2012-10-02
影响因子：
11.1
作者：
Ha, Byung Hak;Davis, Matthew J.;Boggon, Titus J.
通讯作者：
Boggon, Titus J.