Regulation of GTPase function by autophosphorylation.

Autor:	Johnson CW; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Seo HS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Terrell EM; Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA., Yang MH; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., KleinJan F; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Gebregiworgis T; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Gasmi-Seabrook GMC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Geffken EA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Lakhani J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Song K; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Bashyal P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Popow O; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Paulo JA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Liu A; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Mattos C; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA., Marshall CB; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Ikura M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Morrison DK; Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA., Dhe-Paganon S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA., Haigis KM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: Kevin_Haigis@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2022 Mar 03; Vol. 82 (5), pp. 950-968.e14. Date of Electronic Publication: 2022 Feb 23.
DOI:	10.1016/j.molcel.2022.02.011
Abstrakt:	A unifying feature of the RAS superfamily is a conserved GTPase cycle by which these proteins transition between active and inactive states. We demonstrate that autophosphorylation of some GTPases is an intrinsic regulatory mechanism that reduces nucleotide hydrolysis and enhances nucleotide exchange, altering the on/off switch that forms the basis for their signaling functions. Using X-ray crystallography, nuclear magnetic resonance spectroscopy, binding assays, and molecular dynamics on autophosphorylated mutants of H-RAS and K-RAS, we show that phosphoryl transfer from GTP requires dynamic movement of the switch II region and that autophosphorylation promotes nucleotide exchange by opening the active site and extracting the stabilizing Mg 2+ . Finally, we demonstrate that autophosphorylated K-RAS exhibits altered effector interactions, including a reduced affinity for RAF proteins in mammalian cells. Thus, autophosphorylation leads to altered active site dynamics and effector interaction properties, creating a pool of GTPases that are functionally distinct from their non-phosphorylated counterparts. Competing Interests: Declaration of interests K.M.H. is married to a member of Molecular Cell’s Advisory Board. (Copyright © 2022. Published by Elsevier Inc.)
Databáze:	MEDLINE
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