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

Stem cell factor (SCF) is an early-acting hematopoietic cytokine that elici ts multiple biological effects. SCF is dimeric and occurs in soluble and me mbrane-bound forms. It transduces signals by ligand-mediated dimerization o f its receptor, Kit, which is a receptor tyrosine kinase related to the rec eptors for platelet-derived growth factor (PDGF), macrophage colony-stimula ting factor, Flt-3 ligand and vascular endothelial growth factor (VEGF), Al l of these have extracellular ligand-binding portions composed of immunoglo bulin-like repeats. We have determined the crystal structure of selenomethi onyl soluble human SCF at 2.2 Angstrom resolution by multiwavelength anomal ous diffraction phasing. SCF has the characteristic helical cytokine topolo gy, 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 superimposi tion 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 co mplementarity with the Kit counterparts of Flt-1, and a similar model can b e made for the complex of PDGF with its receptor.