VEGFR-2 conformational switch in response to ligand binding
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 an...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-04-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/13876 |
| _version_ | 1811236838849904640 |
|---|---|
| author | Sarvenaz Sarabipour Kurt Ballmer-Hofer Kalina Hristova |
| author_facet | Sarvenaz Sarabipour Kurt Ballmer-Hofer Kalina Hristova |
| author_sort | Sarvenaz Sarabipour |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:16:03Z |
| format | Article |
| id | doaj.art-ce1f47855e6c4417a6791b78cdae14d8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:16:03Z |
| publishDate | 2016-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ce1f47855e6c4417a6791b78cdae14d82022-12-22T03:33:26ZengeLife Sciences Publications LtdeLife2050-084X2016-04-01510.7554/eLife.13876VEGFR-2 conformational switch in response to ligand bindingSarvenaz Sarabipour0https://orcid.org/0000-0001-5097-5509Kurt Ballmer-Hofer1Kalina Hristova2https://orcid.org/0000-0003-4274-4406Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, United StatesLaboratory of Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institute, Villigen, SwitzerlandDepartment of Materials Science and Engineering, Johns Hopkins University, Baltimore, United StatesVEGFR-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.https://elifesciences.org/articles/13876signal transductiontransmembrane domainsdimerizationmodel systems |
| spellingShingle | Sarvenaz Sarabipour Kurt Ballmer-Hofer Kalina Hristova VEGFR-2 conformational switch in response to ligand binding eLife signal transduction transmembrane domains dimerization model systems |
| title | VEGFR-2 conformational switch in response to ligand binding |
| title_full | VEGFR-2 conformational switch in response to ligand binding |
| title_fullStr | VEGFR-2 conformational switch in response to ligand binding |
| title_full_unstemmed | VEGFR-2 conformational switch in response to ligand binding |
| title_short | VEGFR-2 conformational switch in response to ligand binding |
| title_sort | vegfr 2 conformational switch in response to ligand binding |
| topic | signal transduction transmembrane domains dimerization model systems |
| url | https://elifesciences.org/articles/13876 |
| work_keys_str_mv | AT sarvenazsarabipour vegfr2conformationalswitchinresponsetoligandbinding AT kurtballmerhofer vegfr2conformationalswitchinresponsetoligandbinding AT kalinahristova vegfr2conformationalswitchinresponsetoligandbinding |