Premium
Structural basis for stem cell factor–KIT signaling and activation of class III receptor tyrosine kinases
Author(s) -
Liu Heli,
Chen Xiaoyan,
Focia Pamela J,
He Xiaolin
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601545
Subject(s) - biology , receptor tyrosine kinase , receptor protein tyrosine kinases , tyrosine kinase , stem cell factor , proto oncogene proteins c kit , microbiology and biotechnology , kinase , receptor , signal transduction , cancer research , stem cell , biochemistry , haematopoiesis
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.