Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers

Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1772-7. doi: 10.1073/pnas.1323254111. Epub 2014 Jan 21.


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.

Keywords: cancer; cell signaling; receptor tyrosine kinases; structural biology; structure analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Cytoplasm / metabolism
  • Humans
  • Image Processing, Computer-Assisted
  • Models, Molecular
  • Protein Multimerization*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-kit / chemistry*
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Proto-Oncogene Proteins c-kit / ultrastructure
  • Stem Cell Factor / chemistry*
  • Stem Cell Factor / metabolism*


  • Stem Cell Factor
  • Proto-Oncogene Proteins c-kit