Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers.
Using electron microscopy and fitting of crystal structures, we present the 3D reconstruction of ligand-induced dimers of intact receptor tyrosine kinase, KIT. We observe that KIT protomers form close contacts throughout the entire structure of ligand-bound receptor dimers, and that the dimeric receptors adopt multiple, defined conformational states. Interestingly, the homotypic interactions in the membrane proximal Ig-like domain of the extracellular region differ from those observed in the crystal structure of the unconstrained extracellular regions. We observe two prevalent conformations in which the tyrosine kinase domains interact asymmetrically. The asymmetric arrangement of the cytoplasmic regions may represent snapshots of molecular interactions occurring during trans autophosphorylation. Moreover, the asymmetric arrangements may facilitate specific intermolecular interactions necessary for trans phosphorylation of different KIT autophosphorylation sites that are required for stimulation of kinase activity and recruitment of signaling proteins by activated KIT.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
Yarden
Y
Opatowsky
Irit
I
Lax
Francisco
F
Tomé
Franziska
F
Bleichert
Vinzenz M
VM
Unger
Joseph
J
Schlessinger
D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008958:Models, Molecular; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D019089:Stem Cell Factor / Q000737:chemistry* / Q000378:metabolism*
D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit
cancer; cell signaling; receptor tyrosine kinases; structural biology; structure analysis