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