Elucidation of binding determinants and functional consequences of Ras/Raf-cysteine-rich domain interactions

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Raf-1 is a critical downstream target of Ras and contains two distinct domains that bind Ras. The first Ras-binding site (RBS1) in Raf-1 has been shown to be essential for Ras-mediated translocation of Raf-1 to the plasma membrane, whereas the second site, in the Raf-1 cysteine rich domain (Raf-CRD), has been implicated in regulating Raf kinase activity. While recognition elements that promote Ras RBS1 complex formation have been characterized, relatively little is known about Ras/Raf-CRD interactions. In this study, we have characterized interactions important for Ras binding to the Raf-CRB. Reconciling conflicting reports, we found that these interactions are essentially independent of the guanine nucleotide bound state, but instead, are enhanced by post-translational modification of Ras. Specifically, our findings indicate that Res farnesylation is sufficient for stable association of Ras with the Raf-CRD. Furthermore, we have also identified a Raf-CRD variant that is impaired specifically in its interactions with Ras. MMR data also suggests that residues proximal to this mutation site on the Raf-CRD form contacts with Res. This Raf-CRD mutant impairs the ability of Ras to activate Raf kinase, thereby providing additional support that Ras interactions with the Raf-CRD are important for Ras-mediated activation of Raf-1.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2000-07
Language
English
Article Type
Article
Keywords

PROTEIN-KINASE-C; RAF ZINC-FINGER; PLASMA-MEMBRANE; CRYSTAL-STRUCTURE; CONTAINS ZINC; HA-RAS; ACTIVATION; IDENTIFICATION; RESIDUES; TRANSFORMATION

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.275, no.29, pp.22172 - 22179

ISSN
0021-9258
DOI
10.1074/jbc.M000397200
URI
http://hdl.handle.net/10203/73863
Appears in Collection
BiS-Journal Papers(저널논문)
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