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

Yarden Opatowsky, Irit Lax, Francisco Tomé, Franziska Bleichert, Vinzenz M. Unger, Joseph Schlessinger

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish
Pages (from-to)1772-1777
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - 4 Feb 2014


FundersFunder number
National Institutes of HealthR01 AR051448, R01 AR051886, P50 AR054086, R01 GM071590
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR01AR051886


    • Cancer
    • Cell signaling
    • Receptor tyrosine kinases
    • Structural biology
    • Structure analysis


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