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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}
}