PDBsum entry 4xvq

Signaling protein

PDB id: 4xvq

Contents

Protein chain

164 a.a.

Ligands

GNP

GOL

Metals

_MG ×2

Waters ×82

PDB id:

4xvq

Name:

Signaling protein

Title:

H-ras y137e

Structure:

Gtpase hras. Chain: a. Fragment: unp residues 1-166. Synonym: h-ras-1,ha-ras,transforming protein p21,c-h-ras,p21ras. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hras, hras1. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.89Å R-factor: 0.208 R-free: 0.254

Authors:

C.W.Johnson,C.Mattos

Key ref:

P.Y.Ting et al. (2015). Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. Faseb J, 29, 3750-3761. PubMed id: 25999467 DOI: 10.1096/fj.15-271510

Date:

27-Jan-15 Release date: 17-Jun-15

Protein chain

P01112  (RASH_HUMAN) -  GTPase HRas from Homo sapiens

Seq: 189 a.a.

Struc: 164 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP (Bound ligand (Het Group name = GNP) matches with 81.82% similarity) + phosphate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1096/fj.15-271510

Faseb J 29:3750-3761 (2015)

PubMed id: 25999467

Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding.

P.Y.Ting, C.W.Johnson, C.Fang, X.Cao, T.G.Graeber, C.Mattos, J.Colicelli.

ABSTRACT

RAS proteins are signal transduction gatekeepers that mediate cell growth, survival, and differentiation through interactions with multiple effector proteins. The RAS effector RAS- and RAB-interacting protein 1 (RIN1) activates its own downstream effectors, the small GTPase RAB5 and the tyrosine kinase Abelson tyrosine-protein kinase (ABL), to modulate endocytosis and cytoskeleton remodeling. To identify ABL substrates downstream of RAS-to-RIN1 signaling, we examined human HEK293T cells overexpressing components of this pathway. Proteomic analysis revealed several novel phosphotyrosine peptides, including Harvey rat sarcoma oncogene (HRAS)-pTyr(137). Here we report that ABL phosphorylates tyrosine 137 of H-, K-, and NRAS. Increased RIN1 levels enhanced HRAS-Tyr(137) phosphorylation by nearly 5-fold, suggesting that RAS-stimulated RIN1 can drive ABL-mediated RAS modification in a feedback circuit. Tyr(137) is well conserved among RAS orthologs and is part of a transprotein H-bond network. Crystal structures of HRAS(Y137F) and HRAS(Y137E) revealed conformation changes radiating from the mutated residue. Although consistent with Tyr(137) participation in allosteric control of HRAS function, the mutations did not alter intrinsic GTP hydrolysis rates in vitro. HRAS-Tyr(137) phosphorylation enhanced HRAS signaling capacity in cells, however, as reflected by a 4-fold increase in the association of phosphorylated HRAS(G12V) with its effector protein RAF proto-oncogene serine/threonine protein kinase 1 (RAF1). These data suggest that RAS phosphorylation at Tyr(137) allosterically alters protein conformation and effector binding, providing a mechanism for effector-initiated modulation of RAS signaling.-Ting, P. Y., Johnson, C. W., Fang, C., Cao, X., Graeber, T. G., Mattos, C., Colicelli, J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding.