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Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation

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 specia...

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Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: Cell Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572732/
https://www.ncbi.nlm.nih.gov/pubmed/18775312
http://dx.doi.org/10.1016/j.cell.2008.07.047
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author 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
author_facet 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
author_sort Filippakopoulos, Panagis
collection PubMed
description 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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spelling pubmed-25727322008-11-03 Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation 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 Cell Article 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. Cell Press 2008-09-05 /pmc/articles/PMC2572732/ /pubmed/18775312 http://dx.doi.org/10.1016/j.cell.2008.07.047 Text en © 2008 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
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
Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
title Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
title_full Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
title_fullStr Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
title_full_unstemmed Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
title_short Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation
title_sort structural coupling of sh2-kinase domains links fes and abl substrate recognition and kinase activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572732/
https://www.ncbi.nlm.nih.gov/pubmed/18775312
http://dx.doi.org/10.1016/j.cell.2008.07.047
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