Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases

Heli Liu, Xiaoyan Chen, Pamela J. Focia, Xiaolin He*

*Corresponding author for this work

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Stem cell factor (SCF) binds to and activates the KIT receptor, a class III receptor tyrosine kinase (RTK), to stimulate diverse processes including melanogenesis, gametogenesis and hematopoeisis. Dysregulation of KIT activation is associated with many cancers. We report a 2.5 Å crystal structure of the functional core of SCF bound to the extracellular ligand-binding domains of KIT. The structure reveals a 'wrapping' SCF-recognition mode by KIT, in which KIT adopts a bent conformation to facilitate each of its first three immunoglobulin (Ig)-like domains to interact with SCF. Three surface epitopes on SCF, an extended loop, the B and C helices, and the N-terminal segment, contact distinct KIT domains, with two of the epitopes undergoing large conformational changes upon receptor binding. The SCF/KIT complex reveals a unique RTK dimerization assembly, and a novel recognition mode between four-helix bundle cytokines and Ig-family receptors. It serves as a framework for understanding the activation mechanisms of class III RTKs.

Original languageEnglish (US)
Pages (from-to)891-901
Number of pages11
JournalEMBO Journal
Volume26
Issue number3
DOIs
StatePublished - Feb 7 2007

Keywords

  • Cancer
  • Growth factor
  • Protein-protein interaction
  • Signal transduction
  • X-ray crystallography

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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