A Molecular Redox Switch on p21ras STRUCTURAL BASIS FOR THE NITRIC OXIDE-p21ras INTERACTION*

We have identified the site of molecular interaction between nitric oxide (NO) and p21ras responsible for initiation of signal transduction. We found that p21ras was singly S-nitrosylated and localized this modifica-tion to a fragment of p21ras containing Cys118. A mutant form of p21ras, in which Cys118 was changed to a serine residue and termed p21rasC118S, was not S-nitrosylated. NO-related species stimulated guanine nucleotide ex-change on wild-type p21ras, resulting in an active form, but not on p21rasC118S. Furthermore, in contrast to pa-rental Jurkat T cells, NO-related species did not stimu-late mitogen-activated protein kinase activity in cells transfected with p21rasC118S. These data indicate that Cys118 is a critical site of redox regulation of p21ras, and S-nitrosylation of this residue triggers guanine nucleo