Structure of the active core of human stem cell factor and analysis of binding to its receptor kit

EMBO J. 2000 Jul 3;19(13):3192-203. doi: 10.1093/emboj/19.13.3192.

Abstract

Stem cell factor (SCF) is an early-acting hematopoietic cytokine that elicits multiple biological effects. SCF is dimeric and occurs in soluble and membrane-bound forms. It transduces signals by ligand- mediated dimerization of its receptor, Kit, which is a receptor tyrosine kinase related to the receptors for platelet-derived growth factor (PDGF), macrophage colony-stimulating factor, Flt-3 ligand and vascular endothelial growth factor (VEGF). All of these have extracellular ligand-binding portions composed of immunoglobulin-like repeats. We have determined the crystal structure of selenomethionyl soluble human SCF at 2.2 A resolution by multiwavelength anomalous diffraction phasing. SCF has the characteristic helical cytokine topology, but the structure is unique apart from core portions. The SCF dimer has a symmetric 'head-to-head' association. Using various prior observations, we have located potential Kit-binding sites on the SCF dimer. A superimposition of this dimer onto VEGF in its complex with the receptor Flt-1 places the binding sites on SCF in positions of topographical and electrostatic complementarity with the Kit counterparts of Flt-1, and a similar model can be made for the complex of PDGF with its receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cytokines / chemistry
  • Cytokines / metabolism
  • Dimerization
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Stem Cell Factor / chemistry*
  • Stem Cell Factor / metabolism*

Substances

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