Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases.
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 A 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.
Liu
Heli
H
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Chen
Xiaoyan
X
Focia
Pamela J
PJ
He
Xiaolin
X
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D003460:Crystallization; D019281:Dimerization; D051379:Mice / Q000235:genetics*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D019089:Stem Cell Factor / Q000235:genetics* / Q000378:metabolism
D019089:Stem Cell Factor; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit