Raf kinase inhibitor protein (RKIP) negatively regulates the mitogen-activated protein kinase (MAPK) signaling cascade by direct interaction with Raf-1. RKIP belongs to a family of proteins for which a wide range of structures have now been described; all are highly homologous and share a distinctive anion-binding pocket. Using X-ray crystallography, we show that phosphotyrosine can be neatly accommodated within this pocket, and suggest that RKIP proteins may therefore form a novel phosphotyrosine recognition motif. As studies have previously indicated that phosphorylation of the S 338SYY341 region of Raf-1 enhances binding to RKIP leading to suppression of MEK activation, we also propose a model of the Raf-1 DS 338SYpY341W motif bound to RKIP based on the RKIP-pTyr crystal structure. Consistent with reported experimental data, this model suggests phosphorylation of Ser338 may additionally stabilize this complex. Together, these results imply a mechanism for RKIP/Raf-1 interaction in which RKIP regulates Raf-1 activity via direct steric inhibition of the Tyr341 region.
|Number of pages
|Forum on immunopathological diseases & therapeutics
|Published - 7 Jun 2011
- X-ray crystallography