LymphedemaV1, Main, Exploration, bibRecord, 001809

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

Identifieur interne : 001809 ( Main/Exploration ); précédent : 001808; suivant : 001810

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

Auteurs : Matthew W. Parker [États-Unis] ; Andrew D. Linkugel [États-Unis] ; Hira Lal Goel [États-Unis] ; Tingting Wu Gonzalez [États-Unis] ; Arthur M. Mercurio [États-Unis] ; Craig W. Vander Kooi [États-Unis]

Source :

Structure (London, England : 1993) [ 0969-2126 ] ; 2015.

RBID : PMC:4394031

Descripteurs français

English descriptors

KwdEn :
- Amino Acid Sequence, Binding Sites, Humans, Molecular Sequence Data, Neuropilin-2 (chemistry), Neuropilin-2 (metabolism), Protein Binding, Protein Isoforms (chemistry), Protein Isoforms (metabolism), Protein Multimerization, Proteolysis, Vascular Endothelial Growth Factor C (chemistry), Vascular Endothelial Growth Factor C (metabolism).
MESH :
- chemical , chemistry : Neuropilin-2, Protein Isoforms, Vascular Endothelial Growth Factor C.
- chemical , metabolism : Neuropilin-2, Protein Isoforms, Vascular Endothelial Growth Factor C.
- Amino Acid Sequence, Binding Sites, Humans, Molecular Sequence Data, Protein Binding, Protein Multimerization, Proteolysis.

Abstract

SUMMARY

Vascular endothelial growth factor-C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C-terminus in complex with the ligand-binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s₉Nrp2, may function as a selective inhibitor of VEGF-C. We find that s₉Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394031

DOI: 10.1016/j.str.2015.01.018
PubMed: 25752543
PubMed Central: 4394031

Affiliations:

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<term>Neuropilin-2 (metabolism)</term>
<term>Protein Binding</term>
<term>Protein Isoforms (chemistry)</term>
<term>Protein Isoforms (metabolism)</term>
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<term>Facteur de croissance endothéliale vasculaire de type C (métabolisme)</term>
<term>Humains</term>
<term>Isoformes de protéines ()</term>
<term>Isoformes de protéines (métabolisme)</term>
<term>Liaison aux protéines</term>
<term>Multimérisation de protéines</term>
<term>Neuropiline 2 ()</term>
<term>Neuropiline 2 (métabolisme)</term>
<term>Protéolyse</term>
<term>Sites de fixation</term>
<term>Séquence d'acides aminés</term>
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<term>Vascular Endothelial Growth Factor C</term>
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<term>Protein Multimerization</term>
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<front><div type="abstract" xml:lang="en"><title>SUMMARY</title>
<p id="P3">Vascular endothelial growth factor-C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C-terminus in complex with the ligand-binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s<sub>9</sub>
Nrp2, may function as a selective inhibitor of VEGF-C. We find that s<sub>9</sub>
Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.</p>
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Serveur d'exploration sur le lymphœdème

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

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