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Title: Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor

Abstract

Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the ectodomain of KIT, resulting in tyrosine kinase activation. We describe the crystal structure of the entire ectodomain of KIT before and after SCF stimulation. The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. Receptor dimerization is followed by conformational changes that enable lateral interactions between membrane proximal Ig-like domains D4 and D5 of two KIT molecules. Experiments with cultured cells show that KIT activation is compromised by point mutations in amino acids critical for D4-D4 interaction. Moreover, a variety of oncogenic mutations are mapped to the D5-D5 interface. Since key hallmarks of KIT structures, ligand-induced receptor dimerization, and the critical residues in the D4-D4 interface, are conserved in other receptors, the mechanism of KIT stimulation unveiled in this report may apply for other receptor activation.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
929957
Report Number(s):
BNL-80559-2008-JA
Journal ID: ISSN 0092-8674; CELLB5; TRN: US200822%%1121
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cell; Journal Volume: 130
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; AMINO ACIDS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DIMERIZATION; GENE MUTATIONS; INTERACTIONS; MEMBRANES; MOLECULES; MUTATIONS; PHOSPHOTRANSFERASES; RECEPTORS; RESIDUES; STEM CELLS; STIMULATION; TYROSINE; national synchrotron light source

Citation Formats

Yuzawa,S., Opatowsky, Y., Zhang, Z., Mandiyan, V., Lax, I., and Schlessinger, J. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor. United States: N. p., 2007. Web. doi:10.1016/j.cell.2007.05.055.
Yuzawa,S., Opatowsky, Y., Zhang, Z., Mandiyan, V., Lax, I., & Schlessinger, J. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor. United States. doi:10.1016/j.cell.2007.05.055.
Yuzawa,S., Opatowsky, Y., Zhang, Z., Mandiyan, V., Lax, I., and Schlessinger, J. Mon . "Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor". United States. doi:10.1016/j.cell.2007.05.055.
@article{osti_929957,
title = {Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor},
author = {Yuzawa,S. and Opatowsky, Y. and Zhang, Z. and Mandiyan, V. and Lax, I. and Schlessinger, J.},
abstractNote = {Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the ectodomain of KIT, resulting in tyrosine kinase activation. We describe the crystal structure of the entire ectodomain of KIT before and after SCF stimulation. The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. Receptor dimerization is followed by conformational changes that enable lateral interactions between membrane proximal Ig-like domains D4 and D5 of two KIT molecules. Experiments with cultured cells show that KIT activation is compromised by point mutations in amino acids critical for D4-D4 interaction. Moreover, a variety of oncogenic mutations are mapped to the D5-D5 interface. Since key hallmarks of KIT structures, ligand-induced receptor dimerization, and the critical residues in the D4-D4 interface, are conserved in other receptors, the mechanism of KIT stimulation unveiled in this report may apply for other receptor activation.},
doi = {10.1016/j.cell.2007.05.055},
journal = {Cell},
number = ,
volume = 130,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
  • Piebaldism is an autosomal dominant disorder of melanocyte development and is characterized by congenital white parches of skin and hair from which melanocytes are completely absent. A similar disorder of the mouse, 'dominant white spotting' (W), results from mutations of the c-kit proto-oncogene, which encodes the cellular tyrosine kinases receptor for the mast/stem cell growth factor. The authors have identified c-kit gene mutations in three patients with piebaldism. A missense substitution (Phe[r arrow]Leu) at codon 584, within the tyrosine kinases domain, is associated with a severe piebald phenotype, whereas two different frameshifts, within codons 561 and 642, are both associatedmore » with a variable and relatively mild piebald phenotype. This is consistent with a possible 'dominant negative' effect of missense c-kit polypeptides on the function of the dimeric receptor.« less
  • Piebaldism is a rare autosomal dominant disorder of pigmentation, characterized by congenital patches of white skin and hair from which melanocytes are absent. The authors have previously shown that piebaldism can result from missense and frameshift mutations of the KIT proto-oncogene, which encodes the cellular receptor tyrosine kinase for the mast/stem cell growth factor. Here, the authors report two novel KIT mutations associated with human piebaldism. A proximal frameshift is associated with a mild piebald phenotype, and a splice-junction mutation is associated with a highly variable piebald phenotype. They discuss the apparent relationship between the predicted impact of specific KITmore » mutations on total KIT-dependent signal transduction and the severity of the resultant piebald phenotypes. 35 refs., 5 figs.« less
  • Piebaldism is an autosomal dominant genetic disorder characterized by congenital patches of skin and hair from which melanocytes are completely absent. A similar disorder of mouse, dominant white spotting (W), results from mutations of the c-Kit protooncogene, which encodes the receptor for mast/stem cell growth factor. The authors identified a KIT gene mutation in a proband with classic autosomal dominant piebaldism. This mutation results in a Gly {yields} Arg substitution at codon 664, within the tyrosine kinase domain. This substitution was not seen in any normal individuals and was completely linked to the piebald phenotype in the proband's family. Piebaldismmore » in this family thus appears to be the human homologue to dominant white spotting (W) of the mouse.« less