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Title: Direct Contacts Between Extracellular Membrane-Proximal Domains are Required for VEGF Receptor Activation and Cell Signaling

Abstract

Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 {angstrom}. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type Vmore » RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.« less

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
Sponsoring Org.:
DOE - OFFICE OF SCIENCE
OSTI Identifier:
1020070
Report Number(s):
BNL-95441-2011-JA
Journal ID: ISSN 0027-8424; PNASA6; TRN: US201116%%53
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 107; Journal Issue: 5; Journal ID: ISSN 0027-8424
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANGIOGENESIS; CRYSTAL STRUCTURE; DIMERS; GROWTH FACTORS; MUTATIONS; NEOPLASMS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PROTEINS; RESIDUES; RESOLUTION; STEM CELLS; TYROSINE; national synchrotron light source

Citation Formats

Yang, Y, Xie, P, Opatowsky, Y, and Schlessinger, J. Direct Contacts Between Extracellular Membrane-Proximal Domains are Required for VEGF Receptor Activation and Cell Signaling. United States: N. p., 2010. Web. doi:10.1073/pnas.0914052107.
Yang, Y, Xie, P, Opatowsky, Y, & Schlessinger, J. Direct Contacts Between Extracellular Membrane-Proximal Domains are Required for VEGF Receptor Activation and Cell Signaling. United States. https://doi.org/10.1073/pnas.0914052107
Yang, Y, Xie, P, Opatowsky, Y, and Schlessinger, J. 2010. "Direct Contacts Between Extracellular Membrane-Proximal Domains are Required for VEGF Receptor Activation and Cell Signaling". United States. https://doi.org/10.1073/pnas.0914052107.
@article{osti_1020070,
title = {Direct Contacts Between Extracellular Membrane-Proximal Domains are Required for VEGF Receptor Activation and Cell Signaling},
author = {Yang, Y and Xie, P and Opatowsky, Y and Schlessinger, J},
abstractNote = {Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 {angstrom}. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.},
doi = {10.1073/pnas.0914052107},
url = {https://www.osti.gov/biblio/1020070}, journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 5,
volume = 107,
place = {United States},
year = {Fri Jan 01 00:00:00 EST 2010},
month = {Fri Jan 01 00:00:00 EST 2010}
}