Phosphotyrosine recognition by the raf kinase inhibitor protein

Philip C. Simister, Nicholas M. Burton, R. Leo Brady

Research output: Contribution to journalArticle (Academic Journal)

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)59-70
Number of pages12
JournalForum on immunopathological diseases & therapeutics
Volume2
Issue number1
DOIs
Publication statusPublished - 7 Jun 2011

Keywords

  • c-Raf
  • PEBP
  • Phosphotyrosine
  • Raf-1
  • RKIP
  • X-ray crystallography

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