Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling.
Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling.
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DOI：
10.1126/scisignal.2001796
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发表时间：
2011-06-28
影响因子：
7.3
通讯作者：
Yaffe MB
中科院分区：
文献类型：
--
作者：
Alexander J;Lim D;Joughin BA;Hegemann B;Hutchins JR;Ehrenberger T;Ivins F;Sessa F;Hudecz O;Nigg EA;Fry AM;Musacchio A;Stukenberg PT;Mechtler K;Peters JM;Smerdon SJ;Yaffe MB
有丝分裂过程中事件的时间和定位是由有丝分裂酶调节的蛋白质磷酸化控制的，有丝分裂酶包括Aurora A、Aurora B、Nek2、Plk1和细胞周期蛋白依赖的激酶复合体CDK1/Cyclin B。虽然有丝分裂酶可以有重叠的亚细胞定位，但每个激酶似乎都在不同的位点上磷酸化它的底物。为了深入了解局部序列背景在激酶选择性中的相对重要性，确定这五种有丝分裂酶的未知底物，并探索底物识别的潜在机制，我们通过定位扫描定位肽库筛选(PS-OPLS)确定了这些主要有丝分裂酶的最佳底物基序。我们用体外多肽动力学研究验证了单个基序，并使用结构建模在分子水平上合理地选择了关键基序决定残基的激酶特异性。这些激酶的磷酸化位点选择性基序之间的交叉比较揭示了一种进化上保守的互斥机制，在这种机制中，有丝分裂激酶的磷酸化基序的正负选择部分及其亚细胞定位导致了有丝分裂过程中适当的底物以协调的方式定位。
The timing and localization of events during mitosis is controlled by the regulated phosphorylation of proteins by the mitotic kinases, which include Aurora A, Aurora B, Nek2, Plk1, and the cyclin-dependent kinase complex Cdk1/cyclin B. Although mitotic kinases can have overlapping subcellular localizations, each kinase appears to phosphorylate its substrates on distinct sites. To gain insight into the relative importance of local sequence context in kinase selectivity, identify previously unknown substrates of these five mitotic kinases, and explore potential mechanisms for substrate discrimination, we determined the optimal substrate motifs of these major mitotic kinases by Positional Scanning Oriented Peptide Library Screening (PS-OPLS). We verified individual motifs with in vitro peptide kinetic studies and used structural modeling to rationalize the kinase-specific selection of key motif-determining residues at the molecular level. Cross comparisons among the phosphorylation site selectivity motifs of these kinases revealed an evolutionarily conserved mutual exclusion mechanism in which the positively and negatively selected portions of the phosphorylation motifs of mitotic kinases, together with their subcellular localizations, result in proper substrate targeting in a coordinated manner during mitosis.
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影响因子：
4.8
作者：
Ban, R;Irino, Y;Tanaka, H
通讯作者：
Tanaka, H
影响因子：
64.8
作者：
Andersen, JS;Wilkinson, CJ;Mann, M
通讯作者：
Mann, M
DOI：
10.1073/pnas.0708966105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Blethrow, Justin D.;Glavy, Joseph S.;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.
影响因子：
64.8
作者：
Brar, Gloria A.;Kiburz, Brendan M.;Amon, Angelika
通讯作者：
Amon, Angelika
影响因子：
64.5
作者：
Alexandru, G;Uhlmann, F;Nasmyth, K
通讯作者：
Nasmyth, K