Title of article :
Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
Author/Authors :
Panagis Filippakopoulos، نويسنده , , Michael Kofler، نويسنده , , Oliver Hantschel، نويسنده , , Gerald D. Gish، نويسنده , , Florian Grebien، نويسنده , , Eidarus Salah، نويسنده , , Philipp Neudecker، نويسنده , , Lewis E. Kay، نويسنده , , Benjamin E. Turk and Stefan Knapp، نويسنده , , Giulio Superti-Furga، نويسنده , , Tony Pawson، نويسنده , , Stefan Knapp، نويسنده ,
Issue Information :
هفته نامه با شماره پیاپی سال 2008
Pages :
11
From page :
793
To page :
803
Abstract :
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.
Journal title :
CELL
Serial Year :
2008
Journal title :
CELL
Record number :
1019401
Link To Document :
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