Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
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SH2-激酶结构域的结构耦合将FES和ABL底物识别和激酶激活联系起来。
DOI：
10.1016/j.cell.2008.07.047
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发表时间：
2008-09-05
期刊：
影响因子：
64.5
通讯作者：
Knapp, Stefan
中科院分区：
文献类型：
--
作者：
Filippakopoulos, Panagis;Kofler, Michael;Hantschel, Oliver;Gish, Gerald D.;Grebien, Florian;Salah, Eidarus;Neudecker, Philipp;Kay, Lewis E.;Turk, Benjamin E.;Superti-Furga, Giulio;Pawson, Tony;Knapp, Stefan
胞质酪氨酸激酶的SH 2结构域可以增强催化活性和底物识别，但实现这一点的分子机制知之甚少。我们已经解决了人Fes酪氨酸激酶的原型SH 2-激酶单元的结构，其似乎专门用于正信号。在其活性构象中，SH 2结构域与激酶N-末端叶紧密相互作用，并通过必要的包装和静电相互作用将激酶αC螺旋定位在活性构型中。这种相互作用通过配体与SH 2结构域的结合而稳定。我们的数据表明，Fes激酶的激活是密切耦合到通过合作SH 2-激酶-底物相互作用的底物识别。类似地，我们发现，活性Abl激酶的SH 2结构域通过不同的SH 2-激酶界面刺激催化活性和底物磷酸化。因此，活性Fes和Abl原癌激酶的SH 2和催化结构域形成有效酪氨酸激酶信号传导所必需的整合结构。
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase αC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.
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DOI：
10.1016/j.str.2007.10.026
发表时间：
2008-01
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Eswaran J;Bernad A;Ligos JM;Guinea B;Debreczeni JE;Sobott F;Parker SA;Najmanovich R;Turk BE;Knapp S
通讯作者：
Knapp S
影响因子：
5.6
作者：
Bertrand, JA;Thieffine, S;Flocco, M
通讯作者：
Flocco, M
影响因子：
64.5
作者：
Deindl, Sebastian;Kadlecek, Theresa A.;Kuriyan, John
通讯作者：
Kuriyan, John
影响因子：
2.9
作者：
Joseph, Raji E.;Min, Lie;Andreotti, Amy H.
通讯作者：
Andreotti, Amy H.
影响因子：
5.3
作者：
GREER, P;HAIGH, J;PAWSON, T
通讯作者：
PAWSON, T