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

The Biochemical Journal
Sonja LorenzJohn Kuriyan

Abstract

Constitutive activation of the non-receptor tyrosine kinase c-Abl (cellular Abelson tyrosine protein kinase 1, Abl1) in the Bcr (breakpoint cluster region)-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukaemia (CML). Recent studies have indicated that an interaction between the SH2 (Src-homology 2) domain and the N-lobe (N-terminal lobe) of the c-Abl kinase domain (KD) has a critical role in leukaemogenesis [Grebien et al. (2011) Cell 147, 306-319; Sherbenou et al. (2010) Blood 116, 3278-3285]. To dissect the structural basis of this phenomenon, we studied c-Abl constructs comprising the SH2 and KDs in vitro. We present a crystal structure of an SH2-KD construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the KD. 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 KD. That the effects are small compared with the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help...Continue Reading

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Citations

Sep 30, 2016·Journal of Chemical Theory and Computation·Giuseppina La SalaMarco De Vivo
Sep 26, 2017·Nature Structural & Molecular Biology·Tamjeed SalehCharalampos G Kalodimos
Jan 6, 2016·Journal of Cell Science·Aaditya KhatriAnn Marie Pendergast
Sep 6, 2018·Critical Reviews in Biochemistry and Molecular Biology·Neel H ShahJohn Kuriyan
Jan 11, 2018·Journal of the American Chemical Society·Rajesh SontiStephan Grzesiek
Sep 30, 2021·Journal of Medicinal Chemistry·Seung-Hwan KwonHan Seok Ko

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