Journal
EMBO JOURNAL
Volume 26, Issue 3, Pages 891-901Publisher
WILEY
DOI: 10.1038/sj.emboj.7601545
Keywords
cancer; growth factor; protein-protein interaction; signal transduction; X-ray crystallography
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Funding
- NCRR NIH HHS [RR-15301, P41 RR015301] Funding Source: Medline
- NIGMS NIH HHS [R01 GM078055] Funding Source: Medline
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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 angstrom 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.
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