7JII

HRAS A59E GDP

Summary for 7JII

• Entry DOI: 10.2210/pdb7jii/pdb
• Descriptor: GTPase HRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: mutant cancer gtpase, oncoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 38961.78

Authors

Johnson, C.W.,Haigis, K.M. (deposition date: 2020-07-23, release date: 2022-03-02, Last modification date: 2023-10-18)

Primary citation

Johnson, C.W.,Seo, H.S.,Terrell, E.M.,Yang, M.H.,KleinJan, F.,Gebregiworgis, T.,Gasmi-Seabrook, G.M.C.,Geffken, E.A.,Lakhani, J.,Song, K.,Bashyal, P.,Popow, O.,Paulo, J.A.,Liu, A.,Mattos, C.,Marshall, C.B.,Ikura, M.,Morrison, D.K.,Dhe-Paganon, S.,Haigis, K.M.
Regulation of GTPase function by autophosphorylation.
Mol.Cell, 82:950-, 2022

PubMed Abstract: 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. 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.

PubMed: 35202574
DOI: 10.1016/j.molcel.2022.02.011

Experimental method

X-RAY DIFFRACTION (1.532 Å)