Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange
AUTOR(ES)
Williams, Jason G.
FONTE
National Academy of Sciences
RESUMO
Ras is a guanine nucleotide-binding protein that cycles between inactive GDP-bound and active GTP-bound states to regulate a diverse array of cellular processes, including cell growth, apoptosis, and differentiation. The guanine nucleotide-bound state of Ras is tightly maintained by regulatory factors to promote regulated growth control. A class of regulatory molecules that lead to Ras activation are guanine nucleotide exchange factors (GEFs). Ras GEFs bind to Ras and facilitate GDP release, followed by GTP incorporation and Ras activation. Nitric oxide (NO) has also been shown to promote guanine nucleotide exchange (GNE) on Ras and increase cellular Ras-GTP levels, but the process by which NO-mediated GNE occurs is not clear. We initiated NMR structural and biochemical studies to elucidate how nitrosylation of Ras might lead to enhanced GNE. Surprisingly, our studies show that stable S-nitrosylation of Ras at Cys-118, does not affect the structure of Ras, its association with the Ras-binding domain of Raf (a downstream effector of Ras), or GNE rates relative to non-nitrosylated Ras. We have found, however, that the actual chemical process of nitrosylation, rather than the end-product of Ras S-nitrosylation, accounts for the enhanced GNE that we have observed and that has been previously observed by others.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=164454Documentos Relacionados
- Rapid nitric oxide-mediated S-nitrosylation of estrogen receptor: Regulation of estrogen-dependent gene transcription
- Nitric oxide represses inhibitory κB kinase through S-nitrosylation
- S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds.
- S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity
- S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: Further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase