TY - JOUR
T1 - VEGFR-2 conformational switch in response to ligand binding
AU - Sarabipour, Sarvenaz
AU - Ballmer-Hofer, Kurt
AU - Hristova, Kalina
N1 - Funding Information:
This work was supported by grants NIH GM68619, NIH GM95930, and NSF MCB1157687 to KH We thank Drs. Feilim Mac Gabhann and Michael Edidin for many useful discussions and for reading the manuscript prior to publication. We thank Christopher King for help with data analysis. K B-H thanks the Swiss National Science Foundation (grant 31003A-130463) and Oncosuisse (grant OC2 01200- 08-2007) for continuous support of his work.
Publisher Copyright:
© Sarabipour et al.
PY - 2016/4/7
Y1 - 2016/4/7
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.13876
DO - 10.7554/eLife.13876
M3 - Article
C2 - 27052508
AN - SCOPUS:84964501391
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - APRIL2016
M1 - e13876
ER -