2QUZ

Crystal Structure of the activating H-RasK117R mutant in Costello Syndrome, bound to Mg-GDP

Summary for 2QUZ

• Entry DOI: 10.2210/pdb2quz/pdb
• Descriptor: GTPase HRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: hydrolase, gtpase protein, costello syndrome, ras protein, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side: P01112
• Total number of polymer chains: 1
• Total formula weight: 19370.71

Authors

Parret, A.,Scheffzek, K. (deposition date: 2007-08-07, release date: 2007-12-11, Last modification date: 2023-08-30)

Primary citation

Denayer, E.,Parret, A.,Chmara, M.,Schubbert, S.,Vogels, A.,Devriendt, K.,Frijns, J.P.,Rybin, V.,de Ravel, T.J.,Shannon, K.,Cools, J.,Scheffzek, K.,Legius, E.
Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation.
Hum.Mutat., 29:232-239, 2008

PubMed Abstract: Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. De novo heterozygous missense mutations in HRAS codon 12 and 13 disturbing the intrinsic GTP hydrolysis cause Costello syndrome. We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations. Recombinant HRAS p.Lys117Arg demonstrates normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide dissociation rate is increased 80-fold. Consistent with the biochemical data, the crystal structure of the p.Lys117Arg mutant indicates an altered interaction pattern of the side chain that is associated with unfavorable nucleotide binding properties. Together, these data show that a RAS mutation that only perturbs guanine nucleotide binding has similar functional consequences as mutations that impair GTP hydrolysis and causes human disease.

PubMed: 17979197
DOI: 10.1002/humu.20616

Experimental method

X-RAY DIFFRACTION (1.49 Å)