Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding
Identifieur interne : 005059 ( Istex/Corpus ); précédent : 005058; suivant : 005060Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding
Auteurs : Brent A. Appleton ; Ping Wu ; Janice Maloney ; Jianping Yin ; Wei-Ching Liang ; Scott Stawicki ; Kyle Mortara ; Krista K. Bowman ; J Michael Elliott ; William Desmarais ; J Fernando Bazan ; Anil Bagri ; Marc Tessier-Lavigne ; Alexander W. Koch ; Yan Wu ; Ryan J. Watts ; Christian WiesmannSource :
- The EMBO Journal [ 0261-4189 ] ; 2007-11-28.
Abstract
Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.
Url:
DOI: 10.1038/sj.emboj.7601906
Links to Exploration step
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<front><div type="abstract">Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</div>
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<abstractGroup><abstract type="main"><p>Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with <i>in vitro</i>
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<name type="personal"><namePart type="given">J Michael</namePart>
<namePart type="family">Elliott</namePart>
<affiliation>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">William</namePart>
<namePart type="family">Desmarais</namePart>
<affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<description>Present address: Lilly Corporate Center, Indianapolis, IN 46285, USA</description>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">J Fernando</namePart>
<namePart type="family">Bazan</namePart>
<affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Anil</namePart>
<namePart type="family">Bagri</namePart>
<affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Marc</namePart>
<namePart type="family">Tessier‐Lavigne</namePart>
<affiliation>Department of Research Drug Discovery, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Alexander W</namePart>
<namePart type="family">Koch</namePart>
<affiliation>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Yan</namePart>
<namePart type="family">Wu</namePart>
<affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Ryan J</namePart>
<namePart type="family">Watts</namePart>
<affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Christian</namePart>
<namePart type="family">Wiesmann</namePart>
<affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation>
<affiliation>E-mail: chw@gene.com</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<typeOfResource>text</typeOfResource>
<genre type="article" displayLabel="article"></genre>
<originInfo><publisher>John Wiley & Sons, Ltd</publisher>
<place><placeTerm type="text">Chichester, UK</placeTerm>
</place>
<dateIssued encoding="w3cdtf">2007-11-28</dateIssued>
<dateCaptured encoding="w3cdtf">2007-06-28</dateCaptured>
<dateValid encoding="w3cdtf">2007-10-08</dateValid>
<copyrightDate encoding="w3cdtf">2007</copyrightDate>
</originInfo>
<language><languageTerm type="code" authority="rfc3066">en</languageTerm>
<languageTerm type="code" authority="iso639-2b">eng</languageTerm>
</language>
<physicalDescription><internetMediaType>text/html</internetMediaType>
</physicalDescription>
<abstract>Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</abstract>
<note type="additional physical form">Supplementary Figure S1–S8</note>
<subject><genre>keywords</genre>
<topic>neuropilin</topic>
<topic>neuroscience</topic>
<topic>tumorigenesis</topic>
<topic>vasculogenesis</topic>
<topic>X‐ray crystallography</topic>
</subject>
<relatedItem type="host"><titleInfo><title>The EMBO Journal</title>
</titleInfo>
<genre type="journal">journal</genre>
<subject><genre>index-terms</genre>
<topic authorityURI="http://psi.embo.org/14602075/EMBO37">Signal Transduction</topic>
<topic authorityURI="http://psi.embo.org/14602075/EMBO40">Structural Biology</topic>
</subject>
<subject><genre>article-category</genre>
<topic>Article</topic>
</subject>
<identifier type="ISSN">0261-4189</identifier>
<identifier type="eISSN">1460-2075</identifier>
<identifier type="DOI">10.1002/(ISSN)1460-2075</identifier>
<identifier type="PublisherID">EMBJ</identifier>
<part><date>2007</date>
<detail type="volume"><caption>vol.</caption>
<number>26</number>
</detail>
<detail type="issue"><caption>no.</caption>
<number>23</number>
</detail>
<extent unit="pages"><start>4902</start>
<end>4912</end>
<total>11</total>
</extent>
</part>
</relatedItem>
<identifier type="istex">AB5729DC76EAF891407A74B81AF7C8627DDA7FFB</identifier>
<identifier type="DOI">10.1038/sj.emboj.7601906</identifier>
<identifier type="ArticleID">EMBJ7601906</identifier>
<accessCondition type="use and reproduction" contentType="copyright">Copyright © 2013 Wiley Periodicals, IncCopyright © 2007 European Molecular Biology Organization</accessCondition>
<recordInfo><recordContentSource>WILEY</recordContentSource>
<recordOrigin>John Wiley & Sons, Ltd</recordOrigin>
</recordInfo>
</mods>
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