A Combined Approach Reveals a Regulatory Mechanism Coupling Src's Kinase Activity, Localization, and Phosphotransferase-Independent Functions.

Autor:	Ahler E; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, USA., Register AC; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Chakraborty S; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Fang L; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Dieter EM; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Sitko KA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Vidadala RSR; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Trevillian BM; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Golkowski M; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Gelman H; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Stephany JJ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Rubin AF; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, Unversity of Melbourne, Melbourne, VIC, Australia; Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Merritt EA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Fowler DM; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Genetic Networks Program, CIFAR, Toronto, ON, Canada. Electronic address: dfowler@uw.edu., Maly DJ; Department of Chemistry, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: djmaly@uw.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2019 Apr 18; Vol. 74 (2), pp. 393-408.e20. Date of Electronic Publication: 2019 Apr 04.
DOI:	10.1016/j.molcel.2019.02.003
Abstrakt:	Multiple layers of regulation modulate the activity and localization of protein kinases. However, many details of kinase regulation remain incompletely understood. Here, we apply saturation mutagenesis and a chemical genetic method for allosterically modulating kinase global conformation to Src kinase, providing insight into known regulatory mechanisms and revealing a previously undiscovered interaction between Src's SH4 and catalytic domains. Abrogation of this interaction increased phosphotransferase activity, promoted membrane association, and provoked phosphotransferase-independent alterations in cell morphology. Thus, Src's SH4 domain serves as an intramolecular regulator coupling catalytic activity, global conformation, and localization, as well as mediating a phosphotransferase-independent function. Sequence conservation suggests that the SH4 domain regulatory interaction exists in other Src-family kinases. Our combined approach's ability to reveal a regulatory mechanism in one of the best-studied kinases suggests that it could be applied broadly to provide insight into kinase structure, regulation, and function. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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