title: Structure of the active core of human stem cell factor and analysis of binding to its receptor kit.
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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: O
authors.initials: O
authors.lastname: Gurel
authors.forename: E A
authors.initials: EA
authors.lastname: Mendiaz
authors.forename: G W
authors.initials: GW
authors.lastname: Stearns
authors.forename: C L
authors.initials: CL
authors.lastname: Clogston
authors.forename: H S
authors.initials: HS
authors.lastname: Lu
authors.forename: T D
authors.initials: TD
authors.lastname: Osslund
authors.forename: R S
authors.initials: RS
authors.lastname: Syed
authors.forename: K E
authors.initials: KE
authors.lastname: Langley
authors.forename: W A
authors.initials: WA
authors.lastname: Hendrickson
mesh_terms: D000595:Amino Acid Sequence; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D019089:Stem Cell Factor / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit