Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding
Identifieur interne : 002A07 ( Ncbi/Merge ); précédent : 002A06; suivant : 002A08Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding
Auteurs : Brent A. Appleton [États-Unis] ; Ping Wu [États-Unis] ; Janice Maloney [États-Unis] ; Jianping Yin [États-Unis] ; Wei-Ching Liang [États-Unis] ; Scott Stawicki [États-Unis] ; Kyle Mortara [États-Unis] ; Krista K. Bowman [États-Unis] ; J Michael Elliott [États-Unis] ; William Desmarais [États-Unis] ; J Fernando Bazan [États-Unis] ; Anil Bagri [États-Unis] ; Marc Tessier-Lavigne [États-Unis] ; Alexander W. Koch [États-Unis] ; Yan Wu [États-Unis] ; Ryan J. Watts [États-Unis] ; Christian Wiesmann [États-Unis]Source :
- The EMBO Journal [ 0261-4189 ] ; 2007.
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
Url:
DOI: 10.1038/sj.emboj.7601906
PubMed: 17989695
PubMed Central: 2099469
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Appleton</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Ping" sort="Wu, Ping" uniqKey="Wu P" first="Ping" last="Wu">Ping Wu</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Maloney, Janice" sort="Maloney, Janice" uniqKey="Maloney J" first="Janice" last="Maloney">Janice Maloney</name><affiliation wicri:level="1"><nlm:aff id="O2">Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Yin, Jianping" sort="Yin, Jianping" uniqKey="Yin J" first="Jianping" last="Yin">Jianping Yin</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Wei Ching" sort="Liang, Wei Ching" uniqKey="Liang W" first="Wei-Ching" last="Liang">Wei-Ching Liang</name><affiliation wicri:level="1"><nlm:aff id="O3">Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Stawicki, Scott" sort="Stawicki, Scott" uniqKey="Stawicki S" first="Scott" last="Stawicki">Scott Stawicki</name><affiliation wicri:level="1"><nlm:aff id="O3">Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Mortara, Kyle" sort="Mortara, Kyle" uniqKey="Mortara K" first="Kyle" last="Mortara">Kyle Mortara</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Bowman, Krista K" sort="Bowman, Krista K" uniqKey="Bowman K" first="Krista K" last="Bowman">Krista K. 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Koch</name><affiliation wicri:level="1"><nlm:aff id="O4">Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name><affiliation wicri:level="1"><nlm:aff id="O3">Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Watts, Ryan J" sort="Watts, Ryan J" uniqKey="Watts R" first="Ryan J" last="Watts">Ryan J. 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Appleton</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Ping" sort="Wu, Ping" uniqKey="Wu P" first="Ping" last="Wu">Ping Wu</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Maloney, Janice" sort="Maloney, Janice" uniqKey="Maloney J" first="Janice" last="Maloney">Janice Maloney</name><affiliation wicri:level="1"><nlm:aff id="O2">Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Yin, Jianping" sort="Yin, Jianping" uniqKey="Yin J" first="Jianping" last="Yin">Jianping Yin</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Wei Ching" sort="Liang, Wei Ching" uniqKey="Liang W" first="Wei-Ching" last="Liang">Wei-Ching Liang</name><affiliation wicri:level="1"><nlm:aff id="O3">Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Stawicki, Scott" sort="Stawicki, Scott" uniqKey="Stawicki S" first="Scott" last="Stawicki">Scott Stawicki</name><affiliation wicri:level="1"><nlm:aff id="O3">Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Mortara, Kyle" sort="Mortara, Kyle" uniqKey="Mortara K" first="Kyle" last="Mortara">Kyle Mortara</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Bowman, Krista K" sort="Bowman, Krista K" uniqKey="Bowman K" first="Krista K" last="Bowman">Krista K. Bowman</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Elliott, J Michael" sort="Elliott, J Michael" uniqKey="Elliott J" first="J Michael" last="Elliott">J Michael Elliott</name><affiliation wicri:level="1"><nlm:aff id="O4">Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Desmarais, William" sort="Desmarais, William" uniqKey="Desmarais W" first="William" last="Desmarais">William Desmarais</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Bazan, J Fernando" sort="Bazan, J Fernando" uniqKey="Bazan J" first="J Fernando" last="Bazan">J Fernando Bazan</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Bagri, Anil" sort="Bagri, Anil" uniqKey="Bagri A" first="Anil" last="Bagri">Anil Bagri</name><affiliation wicri:level="1"><nlm:aff id="O2">Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Tessier Lavigne, Marc" sort="Tessier Lavigne, Marc" uniqKey="Tessier Lavigne M" first="Marc" last="Tessier-Lavigne">Marc Tessier-Lavigne</name><affiliation wicri:level="1"><nlm:aff id="O5">Department of Research Drug Discovery, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Research Drug Discovery, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Koch, Alexander W" sort="Koch, Alexander W" uniqKey="Koch A" first="Alexander W" last="Koch">Alexander W. Koch</name><affiliation wicri:level="1"><nlm:aff id="O4">Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name><affiliation wicri:level="1"><nlm:aff id="O3">Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Watts, Ryan J" sort="Watts, Ryan J" uniqKey="Watts R" first="Ryan J" last="Watts">Ryan J. Watts</name><affiliation wicri:level="1"><nlm:aff id="O2">Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Wiesmann, Christian" sort="Wiesmann, Christian" uniqKey="Wiesmann C" first="Christian" last="Wiesmann">Christian Wiesmann</name><affiliation wicri:level="1"><nlm:aff id="O1">Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author></analytic><series><title level="j">The EMBO Journal</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><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 <italic>in vitro</italic> 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.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">EMBO J</journal-id><journal-title>The EMBO Journal</journal-title><issn pub-type="ppub">0261-4189</issn><issn pub-type="epub">1460-2075</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">17989695</article-id><article-id pub-id-type="pmc">2099469</article-id><article-id pub-id-type="pii">7601906</article-id><article-id pub-id-type="doi">10.1038/sj.emboj.7601906</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding</article-title><alt-title alt-title-type="short">Crystal structures of Nrp/Fab complexes</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Appleton</surname><given-names>Brent A</given-names></name><xref ref-type="aff" rid="O1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Ping</given-names></name><xref ref-type="aff" rid="O1">1</xref></contrib><contrib contrib-type="author"><name><surname>Maloney</surname><given-names>Janice</given-names></name><xref ref-type="aff" rid="O2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yin</surname><given-names>JianPing</given-names></name><xref ref-type="aff" rid="O1">1</xref></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Wei-Ching</given-names></name><xref ref-type="aff" rid="O3">3</xref></contrib><contrib contrib-type="author"><name><surname>Stawicki</surname><given-names>Scott</given-names></name><xref ref-type="aff" rid="O3">3</xref></contrib><contrib contrib-type="author"><name><surname>Mortara</surname><given-names>Kyle</given-names></name><xref ref-type="aff" rid="O1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bowman</surname><given-names>Krista K</given-names></name><xref ref-type="aff" rid="O1">1</xref></contrib><contrib contrib-type="author"><name><surname>Elliott</surname><given-names>J Michael</given-names></name><xref ref-type="aff" rid="O4">4</xref></contrib><contrib contrib-type="author"><name><surname>Desmarais</surname><given-names>William</given-names></name><xref ref-type="aff" rid="O1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Bazan</surname><given-names>J Fernando</given-names></name><xref ref-type="aff" rid="O1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bagri</surname><given-names>Anil</given-names></name><xref ref-type="aff" rid="O2">2</xref></contrib><contrib contrib-type="author"><name><surname>Tessier-Lavigne</surname><given-names>Marc</given-names></name><xref ref-type="aff" rid="O5">5</xref></contrib><contrib contrib-type="author"><name><surname>Koch</surname><given-names>Alexander W</given-names></name><xref ref-type="aff" rid="O4">4</xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="O3">3</xref></contrib><contrib contrib-type="author"><name><surname>Watts</surname><given-names>Ryan J</given-names></name><xref ref-type="aff" rid="O2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wiesmann</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="O1">1</xref><xref ref-type="corresp" rid="c1">a</xref></contrib><aff id="O1"><label>1</label>Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA</aff><aff id="O2"><label>2</label>Department of Tumor Biology & Angiogenesis, Genentech, Inc., South San Francisco, CA, USA</aff><aff id="O3"><label>3</label>Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA</aff><aff id="O4"><label>4</label>Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA, USA</aff><aff id="O5"><label>5</label>Department of Research Drug Discovery, Genentech, Inc., South San Francisco, CA, USA</aff></contrib-group><author-notes><corresp id="c1"><label>a</label>Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 7484; Fax: +1 650 225 3734; E-mail: <email>chw@gene.com</email></corresp><fn id="n1"><label>*</label><p>Present address: Lilly Corporate Center, Indianapolis, IN 46285, USA</p></fn></author-notes><pub-date pub-type="ppub"><day>28</day><month>11</month><year>2007</year></pub-date><pub-date pub-type="epub"><day>08</day><month>11</month><year>2007</year></pub-date><volume>26</volume><issue>23</issue><fpage>4902</fpage><lpage>4912</lpage><history><date date-type="received"><day>28</day><month>06</month><year>2007</year></date><date date-type="accepted"><day>8</day><month>10</month><year>2007</year></date></history><copyright-statement>Copyright © 2007, European Molecular Biology Organization</copyright-statement><copyright-year>2007</copyright-year><abstract><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 <italic>in vitro</italic> 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.</p></abstract><kwd-group><kwd>neuropilin</kwd><kwd>neuroscience</kwd><kwd>tumorigenesis</kwd><kwd>vasculogenesis</kwd><kwd>X-ray crystallography</kwd></kwd-group><counts><page-count count="11"></page-count></counts></article-meta></front><floats-wrap><fig id="f1"><label>Figure 1</label><caption><p>VEGF does not block Sema3A-induced growth cone collapse of DRG neurons. (<bold>A</bold>) Images of axon growth cones. Untreated dorsal root ganglia (DRG) have large actin-rich growth cones (arrowheads) that are significantly reduced in number upon addition of Sema3A. Anti-Nrp antibodies were added at 50 μg/ml; Sema3A was added at 2.2 nM. Only anti-panNrp<sup>A</sup> blocks Sema3A-mediated collapse. (<bold>B</bold>) Quantification of Sema3A-induced growth cone collapse. The percentage of collapsed growth cones were calculated by counting collapsed and uncollapsed growth cones (<italic>N</italic>=4 explants per condition). Error bars represent standard error of the mean.</p></caption><graphic xlink:href="7601906f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><p>Summary of the neuropilin crystal structures. (<bold>A</bold>) The Nrp ectodomain is comprised of tandem CUB (a1a2), tandem coagulation factor V/VIII (b1b2), and one MAM (c) domain. Cartoon representation of the seven crystal structures presented in this report with the resolution limits listed below. Magenta spheres indicate a bound calcium ion in the a2 domain. (<bold>B</bold>) Sequence alignment of the a1a2b1b2 domains of human Nrp1 and Nrp2. Secondary structure elements refer to the Nrp2 a1a2b1b2 structure (blue, a1; green, a2; yellow, b1; red, b2) and are named according to conventions adopted for the spermadhesin CUB domain (<xref ref-type="bibr" rid="b47">Romero <italic>et al</italic>, 1997</xref>) and the coagulation factor V C2 domain (<xref ref-type="bibr" rid="b33">Macedo-Ribeiro <italic>et al</italic>, 1999</xref>). Residues boxed in blue and yellow delineate the antibody epitopes for anti-panNrp<sup>A</sup> and anti-Nrp1<sup>B</sup>, respectively. Amino acids highlighted in orange indicate the Ca<sup>2+</sup>-binding site in a2, while residues in red represent a putative Ca<sup>2+</sup>-binding site in the a1 domain. Residues shaded in green highlight the positions of amino acid that when substituted disrupt interactions between Sema3A and Nrp1 (<xref ref-type="bibr" rid="b22">Gu <italic>et al</italic>, 2002</xref>). This alignment was produced with EsPript (<xref ref-type="bibr" rid="b19">Gouet <italic>et al</italic>, 2003</xref>).</p></caption><graphic xlink:href="7601906f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><p>Overall domain architecture of neuropilins. (<bold>A</bold>) Domain organization of Nrp2 (blue, a1; green, a2; yellow, b1; red, b2) in complex with the Fab fragment of anti-panNrp<sup>A</sup> (tan, heavy chain; gray, light chain). <italic>N</italic>-glycosylated residues are indicated in magenta. (<bold>B</bold>) Ribbon representation of the Nrp a2b1b2 structures; the orange spheres highlight a bound calcium ion. (<bold>C</bold>) Superposition of the Nrp2/Fab complex from two different crystal forms based on the a2b1b2 domains. Note the poor superposition of the a1 domains (yellow arrows) in comparison to the a2b1b2 region (black arrows). Structure figures were produced with PyMol (<ext-link ext-link-type="uri" xlink:href="http://www.pymol.org">http://www.pymol.org</ext-link>).</p></caption><graphic xlink:href="7601906f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><p>Molecular details of the neuropilin CUB domains. (<bold>A</bold>) In the a2b1b2 structures, the a2 domain includes a bound calcium ion (orange). The Nrp a1 (panel C) and a2 domains lack the β1 strand found in spermadhesin. (<bold>B</bold>) The calcium ion of the Nrp1 a2 domain is coordinated by three negatively charged amino acids, two main-chain carbonyl oxygens, and a water molecule. These interactions are highly conserved among Nrps (<xref ref-type="supplementary-material" rid="S1">Supplementary Figures S2 and S3</xref>). (<bold>C</bold>) (left panel) Amino acids are colored according to the percentage of solvent-accessible surface that is buried at the Nrp2/Fab interface (red, 75–100%; orange, 50–74%; yellow, 25–49%). Anti-panNrp<sup>A</sup> is crossreactive for Nrp1 and Nrp2, and 11 of the 14 residues in the structural epitope are identical (black text, identical; white text, nonconserved; asterisks indicate residues in which the side chain points toward the a1 protein core). Residues outlined in green indicate the position of amino acids that when replaced were shown to abrogate binding between Nrp1 and Sema3A (<xref ref-type="bibr" rid="b22">Gu <italic>et al</italic>, 2002</xref>). (right panel) The C<sub>α</sub> atoms of these amino-acid substitutions are indicated as green spheres. C<sub>α</sub> atoms shaded in purple represent a putative calcium-binding site. (<bold>D</bold>) The anti-panNrp<sup>A</sup>/Nrp2 interface. Nrp2 is shown as a molecular surface with local concentrations of charged residues colored blue (basic) or red (acidic) as calculated by PyMol. The antibody contact residues are dominated by aromatic resides from CDRs H2, H3, and L3.</p></caption><graphic xlink:href="7601906f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><p>Features of the Nrp VEGF- and heparin-binding domains. (<bold>A</bold>) The molecular surface of the rat (PDB code 2ORZ) (<xref ref-type="bibr" rid="b55">Vander Kooi <italic>et al</italic>, 2007</xref>) and human b1b2 crystal structures are colored as described in <xref ref-type="fig" rid="f4">Figure 4D</xref>. Green arrows indicate an acidic groove that is formed by the ‘spikes' in the b1 domain (<xref ref-type="supplementary-material" rid="S1">Supplementary Figure S5</xref>); this feature forms the Tuftsin-binding site of rat Nrp1. Yellow arrows indicate the approximate location of the heparin-binding patch. (<bold>B</bold>) The sequence conservation (green, 100%; yellow, ⩾75%) of the b1b2 domains among 12 Nrps (<xref ref-type="supplementary-material" rid="S1">Supplementary Figure S3</xref>) was mapped onto the surface of the human Nrp1 b1b2 structure. Two highly conserved patches are delineated in red. Residues outlined in cyan indicate those residues that contact the Fab in the anti-Nrp1<sup>B</sup>-Fab/b1 complex. The a2 domain (tan) is shown by using a superposition of the b1b2 and a2b1b2 structures from Nrp1. (<bold>C</bold>) Ribbon representation of the anti-Nrp1<sup>B</sup>–Fab/b1 complex (yellow, b1; orange, heavy chain; gray, light chain). (<bold>D</bold>) The anti-Nrp1<sup>B</sup>/b1 interface. The b1 domain is depicted as a molecular surface with a green arrow indicating the Tuftsin/VEGF tail-binding groove. Only CDRs H3 and L1 contact b1.</p></caption><graphic xlink:href="7601906f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><p>A Nrp2 crystallographic dimer suggests models for VEGF and Sema3 binding. (<bold>A</bold>) Nrp2 forms a saddle-shaped dimer in both crystal forms of the Nrp2/Fab complex. This figure highlights the Nrp2 a1a2b1b2 domains from the monoclinic crystal form of the Fab complex. The putative VEGF tail-, heparin-, and semaphorin-binding sites are indicated. (<bold>B</bold>) Potential models of VEGF/Nrp and semaphorin/Nrp complexes based on the Nrp a1-mediated dimer in the crystal structures.</p></caption><graphic xlink:href="7601906f6"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><p>Data collection and refinement statistics</p></caption><table frame="hsides" rules="groups" border="1" width="85%"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50">Nrp1 b1b2</th><th align="center" valign="top" charoff="50">Nrp1 a2b1b2</th><th align="center" valign="top" charoff="50">Nrp1 b1/Fab</th><th align="center" valign="top" charoff="50">Nrp2 b1b2</th><th align="center" valign="top" charoff="50">Nrp2 a2b1b2</th><th align="center" valign="top" charoff="50">Nrp2 a1a2b1b2/Fab</th><th align="center" valign="top" charoff="50">Nrp2 a1a2b1b2/Fab</th></tr></thead><tbody valign="top"><tr><td colspan="8" align="left" valign="top" charoff="50"><italic>Data collection</italic></td></tr><tr><td align="left" valign="top" charoff="50"> PDB code</td><td align="center" valign="top" charoff="50">2QQI</td><td align="center" valign="top" charoff="50">2QQM</td><td align="center" valign="top" charoff="50">2QQN</td><td align="center" valign="top" charoff="50">2QQJ</td><td align="center" valign="top" charoff="50">2QQO</td><td align="center" valign="top" charoff="50">2QQK</td><td align="center" valign="top" charoff="50">2QQL</td></tr><tr><td align="left" valign="top" charoff="50"> Space group</td><td align="center" valign="top" charoff="50">P2<sub>1</sub>2<sub>1</sub>2<sub>1</sub></td><td align="center" valign="top" charoff="50">P2<sub>1</sub></td><td align="center" valign="top" charoff="50">H3</td><td align="center" valign="top" charoff="50">P2<sub>1</sub>2<sub>1</sub>2<sub>1</sub></td><td align="center" valign="top" charoff="50">P2<sub>1</sub></td><td align="center" valign="top" charoff="50">C2</td><td align="center" valign="top" charoff="50">P3<sub>2</sub>21</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="8" align="left" valign="top" charoff="50"> Cell dimensions</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>a, b, c</italic> (Å)</td><td align="center" valign="top" charoff="50">65.9, 67.0, 74.7</td><td align="center" valign="top" charoff="50">53.2, 68.2, 66.6</td><td align="center" valign="top" charoff="50">214, 214, 45.5</td><td align="center" valign="top" charoff="50">36.5, 70.5, 122</td><td align="center" valign="top" charoff="50">50.1, 193, 66.2</td><td align="center" valign="top" charoff="50">148, 106, 92.4</td><td align="center" valign="top" charoff="50">121, 121, 203</td></tr><tr><td align="left" valign="top" charoff="50"> α, β, γ (deg)</td><td align="center" valign="top" charoff="50">90, 90, 90</td><td align="center" valign="top" charoff="50">90, 102, 90</td><td align="center" valign="top" charoff="50">90, 90, 120</td><td align="center" valign="top" charoff="50">90, 90, 90</td><td align="center" valign="top" charoff="50">90, 90.1, 90</td><td align="center" valign="top" charoff="50">90, 98.8, 90</td><td align="center" valign="top" charoff="50">90, 90, 120</td></tr><tr><td align="left" valign="top" charoff="50"> Resolution (Å)</td><td align="center" valign="top" charoff="50">50–1.8</td><td align="center" valign="top" charoff="50">50–2.0</td><td align="center" valign="top" charoff="50">50–2.2</td><td align="center" valign="top" charoff="50">50–1.95</td><td align="center" valign="top" charoff="50">50–2.3</td><td align="center" valign="top" charoff="50">50–2.75</td><td align="center" valign="top" charoff="50">50–3.1</td></tr><tr><td align="left" valign="top" charoff="50"> No. of reflections</td><td align="center" valign="top" charoff="50">30 653</td><td align="center" valign="top" charoff="50">30 901</td><td align="center" valign="top" charoff="50">39 195</td><td align="center" valign="top" charoff="50">23 691</td><td align="center" valign="top" charoff="50">52 659</td><td align="center" valign="top" charoff="50">36 321</td><td align="center" valign="top" charoff="50">31 929</td></tr><tr><td align="left" valign="top" charoff="50"> Completeness (%)</td><td align="center" valign="top" charoff="50">97.6 (99.3)</td><td align="center" valign="top" charoff="50">97.5 (88.7)</td><td align="center" valign="top" charoff="50">99.0 (98.0)</td><td align="center" valign="top" charoff="50">99.8 (99.9)</td><td align="center" valign="top" charoff="50">94.5 (85.6)</td><td align="center" valign="top" charoff="50">99.6 (100)</td><td align="center" valign="top" charoff="50">99.6 (98.9)</td></tr><tr><td align="left" valign="top" charoff="50"> Redundancy</td><td align="center" valign="top" charoff="50">4.6 (4.6)</td><td align="center" valign="top" charoff="50">3.5 (3.0)</td><td align="center" valign="top" charoff="50">4.4 (3.6)</td><td align="center" valign="top" charoff="50">5.3 (5.2)</td><td align="center" valign="top" charoff="50">4.2 (4.1)</td><td align="center" valign="top" charoff="50">4.2 (4.2)</td><td align="center" valign="top" charoff="50">3.8 (3.6)</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>R</italic><sub>sym</sub></td><td align="center" valign="top" charoff="50">5.0 (51.5)</td><td align="center" valign="top" charoff="50">8.6 (32.2)</td><td align="center" valign="top" charoff="50">9.6 (48.5)</td><td align="center" valign="top" charoff="50">8.9 (53.0)</td><td align="center" valign="top" charoff="50">5.6 (34.4)</td><td align="center" valign="top" charoff="50">10.4 (52.7)</td><td align="center" valign="top" charoff="50">6.1 (51.5)</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>I</italic>/σ<italic>I</italic></td><td align="center" valign="top" charoff="50">26.9 (3.2)</td><td align="center" valign="top" charoff="50">13.8 (2.4)</td><td align="center" valign="top" charoff="50">14.3 (2.2)</td><td align="center" valign="top" charoff="50">16.8 (3.1)</td><td align="center" valign="top" charoff="50">20.7 (3.7)</td><td align="center" valign="top" charoff="50">10.9 (3.3)</td><td align="center" valign="top" charoff="50">18.3 (2.6)</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="8" align="left" valign="top" charoff="50"><italic>Refinement</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Resolution (Å)</td><td align="center" valign="top" charoff="50">20–1.8</td><td align="center" valign="top" charoff="50">20–2.0</td><td align="center" valign="top" charoff="50">20–2.2</td><td align="center" valign="top" charoff="50">20–1.95</td><td align="center" valign="top" charoff="50">20–2.3</td><td align="center" valign="top" charoff="50">30–2.75</td><td align="center" valign="top" charoff="50">30–3.1</td></tr><tr><td align="left" valign="top" charoff="50"> No. of reflections</td><td align="center" valign="top" charoff="50">29 018</td><td align="center" valign="top" charoff="50">29 213</td><td align="center" valign="top" charoff="50">37 085</td><td align="center" valign="top" charoff="50">22 404</td><td align="center" valign="top" charoff="50">49 667</td><td align="center" valign="top" charoff="50">34 487</td><td align="center" valign="top" charoff="50">30 265</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>R</italic><sub>work</sub><italic>/R</italic><sub>free</sub></td><td align="center" valign="top" charoff="50">0.159/0.201</td><td align="center" valign="top" charoff="50">0.183/0.243</td><td align="center" valign="top" charoff="50">0.159/0.207</td><td align="center" valign="top" charoff="50">0.172/0.235</td><td align="center" valign="top" charoff="50">0.185/0.239</td><td align="center" valign="top" charoff="50">0.186/0.243</td><td align="center" valign="top" charoff="50">0.188/0.232</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>No. of atoms</italic></td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Protein</td><td align="center" valign="top" charoff="50">2549</td><td align="center" valign="top" charoff="50">3459</td><td align="center" valign="top" charoff="50">4540</td><td align="center" valign="top" charoff="50">2509</td><td align="center" valign="top" charoff="50">6813</td><td align="center" valign="top" charoff="50">7593</td><td align="center" valign="top" charoff="50">7740</td></tr><tr><td align="left" valign="top" charoff="50"> Ligand/ion</td><td align="center" valign="top" charoff="50">6</td><td align="center" valign="top" charoff="50">25</td><td align="center" valign="top" charoff="50">12</td><td align="center" valign="top" charoff="50">6</td><td align="center" valign="top" charoff="50">34</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Sugar</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">76</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">28</td><td align="center" valign="top" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Water</td><td align="center" valign="top" charoff="50">282</td><td align="center" valign="top" charoff="50">194</td><td align="center" valign="top" charoff="50">249</td><td align="center" valign="top" charoff="50">239</td><td align="center" valign="top" charoff="50">365</td><td align="center" valign="top" charoff="50">0</td><td align="center" valign="top" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> B-factors (Å<sup>2</sup>)</td><td align="center" valign="top" charoff="50">26.6</td><td align="center" valign="top" charoff="50">36.3</td><td align="center" valign="top" charoff="50">33.2</td><td align="center" valign="top" charoff="50">22.5</td><td align="center" valign="top" charoff="50">31.8</td><td align="center" valign="top" charoff="50">74.9</td><td align="center" valign="top" charoff="50">97.1</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="8" align="left" valign="top" charoff="50"> R.m.s. deviations</td></tr><tr><td align="left" valign="top" charoff="50"> Bond lengths (Å)</td><td align="center" valign="top" charoff="50">0.014</td><td align="center" valign="top" charoff="50">0.012</td><td align="center" valign="top" charoff="50">0.013</td><td align="center" valign="top" charoff="50">0.013</td><td align="center" valign="top" charoff="50">0.013</td><td align="center" valign="top" charoff="50">0.011</td><td align="center" valign="top" charoff="50">0.010</td></tr><tr><td align="left" valign="top" charoff="50"> Bond angles (deg)</td><td align="center" valign="top" charoff="50">1.5</td><td align="center" valign="top" charoff="50">1.5</td><td align="center" valign="top" charoff="50">1.4</td><td align="center" valign="top" charoff="50">1.5</td><td align="center" valign="top" charoff="50">1.4</td><td align="center" valign="top" charoff="50">1.3</td><td align="center" valign="top" charoff="50">1.3</td></tr><tr><td colspan="8" align="left" valign="top" charoff="50">One crystal was used for data collection for each structure. Values in parentheses refer to the highest-resolution shell.</td></tr></tbody></table><graphic alternate-form-of="t1" xlink:href="7601906t1"></graphic></table-wrap></floats-wrap></pmc><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Appleton, Brent A" sort="Appleton, Brent A" uniqKey="Appleton B" first="Brent A" last="Appleton">Brent A. Appleton</name></noRegion><name sortKey="Bagri, Anil" sort="Bagri, Anil" uniqKey="Bagri A" first="Anil" last="Bagri">Anil Bagri</name><name sortKey="Bazan, J Fernando" sort="Bazan, J Fernando" uniqKey="Bazan J" first="J Fernando" last="Bazan">J Fernando Bazan</name><name sortKey="Bowman, Krista K" sort="Bowman, Krista K" uniqKey="Bowman K" first="Krista K" last="Bowman">Krista K. Bowman</name><name sortKey="Desmarais, William" sort="Desmarais, William" uniqKey="Desmarais W" first="William" last="Desmarais">William Desmarais</name><name sortKey="Elliott, J Michael" sort="Elliott, J Michael" uniqKey="Elliott J" first="J Michael" last="Elliott">J Michael Elliott</name><name sortKey="Koch, Alexander W" sort="Koch, Alexander W" uniqKey="Koch A" first="Alexander W" last="Koch">Alexander W. Koch</name><name sortKey="Liang, Wei Ching" sort="Liang, Wei Ching" uniqKey="Liang W" first="Wei-Ching" last="Liang">Wei-Ching Liang</name><name sortKey="Maloney, Janice" sort="Maloney, Janice" uniqKey="Maloney J" first="Janice" last="Maloney">Janice Maloney</name><name sortKey="Mortara, Kyle" sort="Mortara, Kyle" uniqKey="Mortara K" first="Kyle" last="Mortara">Kyle Mortara</name><name sortKey="Stawicki, Scott" sort="Stawicki, Scott" uniqKey="Stawicki S" first="Scott" last="Stawicki">Scott Stawicki</name><name sortKey="Tessier Lavigne, Marc" sort="Tessier Lavigne, Marc" uniqKey="Tessier Lavigne M" first="Marc" last="Tessier-Lavigne">Marc Tessier-Lavigne</name><name sortKey="Watts, Ryan J" sort="Watts, Ryan J" uniqKey="Watts R" first="Ryan J" last="Watts">Ryan J. Watts</name><name sortKey="Wiesmann, Christian" sort="Wiesmann, Christian" uniqKey="Wiesmann C" first="Christian" last="Wiesmann">Christian Wiesmann</name><name sortKey="Wu, Ping" sort="Wu, Ping" uniqKey="Wu P" first="Ping" last="Wu">Ping Wu</name><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name><name sortKey="Yin, Jianping" sort="Yin, Jianping" uniqKey="Yin J" first="Jianping" last="Yin">Jianping Yin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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