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  Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity

Lorenz, S., Deng, P., Hantschel, O., Superti-Furga, G., & Kuriyan, J. (2015). Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity. Biochemical Journal, 468(2), 283-291. doi:10.1042/BJ20141492.

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Lorenz, Sonja1, 2, Author                 
Deng, Patricia, Author
Hantschel, Oliver, Author
Superti-Furga, Giulio, Author
Kuriyan, John, Author
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1Research Group Ubiquitin Signaling Specificity, MPI for Biophysical Chemistry, Max Planck Society, ou_3337583              
2External Organizations, ou_persistent22              

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Free keywords: Abl, tyrosine kinase, SH2 domain, imatinib, dasatinib, CML
 Abstract: Constitutive activation of the non-receptor tyrosine kinase c-Abl (Abl1) in the Bcr-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukemia. Recent studies have indicated that an interaction between the SH2 domain and the N-lobe of the c-Abl kinase domain has a critical role in leukemogenesis. To dissect the structural basis of this phenomenon we studied c-Abl constructs comprising the SH2 and kinase domains in vitro. We present a crystal structure of an SH2-kinase domain construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the kinase domain. We show that the presence of the SH2 domain enhances kinase activity moderately and that this effect depends on contacts in the SH2-N-lobe interface and is abrogated by specific mutations. Consistently, formation of the interface decreases slightly the association rate of imatinib with the kinase domain. That the effects are small compared to the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help disassemble the autoinhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1042/BJ20141492
 Degree: -

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Title: Biochemical Journal
Source Genre: Journal
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Publ. Info: London : Published by Portland Press on behalf of the Biochemical Society.
Pages: - Volume / Issue: 468 (2) Sequence Number: - Start / End Page: 283 - 291 Identifier: ISSN: 0264-6021
CoNE: https://pure.mpg.de/cone/journals/resource/110992357308158