Crystal structure of human stem cell factor: Implication for stem cell factor receptor dimerization and activation

Crystal structure of human stem cell factor: Implication for stem cell factor receptor dimerization and activation

Departments of ^*Pharmacology and ^§Biochemistry and ^‡Skirball Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016; and ^†Argonne National Laboratory, Argonne, IL 60439

Contributed by Joseph Schlessinger

Abstract

Stem cell factor (SCF) plays important roles in hematopoiesis and the survival, proliferation, and differentiation of mast cells, melanocytes, and germ cells. SCF mediates its biological effects by binding to and activating a receptor tyrosine kinase designated c-kit or SCF receptor. In this report we describe the 2.3-Å crystal structure of the functional core of recombinant human SCF. SCF is a noncovalent homodimer composed of two slightly wedged protomers. Each SCF protomer exhibits an antiparallel four-helix bundle fold. Dimerization is mediated by extensive polar and nonpolar interactions between the two protomers with a large buried surface area. Finally, we have identified a hydrophobic crevice and a charged region at the tail of each protomer that functions as a potential receptor-binding site. On the basis of these observations, a model for SCF⋅c-kit complex formation and dimerization is proposed.

Footnotes

↵ ¶ To whom reprint requests should be addressed at: Departments of Pharmacology and Biochemistry and Skirball Institute, NYU Medical Center, 550 First Avenue, New York, NY 10016. E-mail: g967758{at}med.nyu.edu or kong{at}saturn.med.nyu.edu.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID code 1EXZ).
Abbreviations:

SCF,

stem cell factor;

SCFR,

SCF receptor;

RTK,

receptor tyrosine kinase;

PDGF,

platelet-derived growth factor;

M-CSF,

macrophage colony-stimulating factor