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

Publication Type:

Journal Article

Authors:

Liu, Heli; Chen, Xiaoyan; Focia, Pamela J; He, Xiaolin

Source:

EMBO J, Volume 26, Issue 3, p.891-901 (2007)

Keywords:

Amino Acid Sequence, Animals, Base Sequence, Cloning, Molecular, Crystallization, Dimerization, Mice, Models, Molecular, Molecular Conformation, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-kit, Sequence Analysis, DNA, Signal Transduction, Stem Cell Factor

Abstract:

<p>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.</p>