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VEGFR-2 conformational switch in response to ligand binding.
Journal article

VEGFR-2 conformational switch in response to ligand binding.

  • Sarabipour S Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United States.
  • Ballmer-Hofer K Laboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institute, Villigen, Switzerland.
  • Hristova K Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United States.
  • 2016-04-08
Published in:
  • eLife. - 2016
biochemistry
biophysics
dimerization
model systems
signal transduction
structural biology
transmembrane domains
Humans
Ligands
Mutant Proteins
Phosphorylation
Protein Conformation
Protein Domains
Protein Multimerization
Vascular Endothelial Growth Factor Receptor-2
English VEGFR-2 is the primary regulator of angiogenesis, the development of new blood vessels from pre-existing ones. VEGFR-2 has been hypothesized to be monomeric in the absence of bound ligand, and to undergo dimerization and activation only upon ligand binding. Using quantitative FRET and biochemical analysis, we show that VEGFR-2 forms dimers also in the absence of ligand when expressed at physiological levels, and that these dimers are phosphorylated. Ligand binding leads to a change in the TM domain conformation, resulting in increased kinase domain phosphorylation. Inter-receptor contacts within the extracellular and TM domains are critical for the establishment of the unliganded dimer structure, and for the transition to the ligand-bound active conformation. We further show that the pathogenic C482R VEGFR-2 mutant, linked to infantile hemangioma, promotes ligand-independent signaling by mimicking the structure of the ligand-bound wild-type VEGFR-2 dimer.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/44751
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