By Interacting with the C-terminal Phe of Apelin, Phe255 and Trp259 in Helix VI of the Apelin Receptor Are Critical for Internalization*
Identifieur interne : 000060 ( Pmc/Curation ); précédent : 000059; suivant : 000061By Interacting with the C-terminal Phe of Apelin, Phe255 and Trp259 in Helix VI of the Apelin Receptor Are Critical for Internalization*
Auteurs : Xavier Iturrioz ; Romain Gerbier [France] ; Vincent Leroux ; Rodrigo Alvear-Perez ; Bernard Maigret ; Catherine Llorens-CortesSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2010.
Abstract
Apelin is the endogenous ligand of the orphan seven-transmembrane domain (TM) G protein-coupled receptor APJ. Apelin is involved in the regulation of body fluid homeostasis and cardiovascular functions. We previously showed the importance of the C-terminal Phe of apelin 17 (K17F) in the hypotensive activity of this peptide. Here, we show either by deleting the Phe residue (K16P) or by substituting it by an Ala (K17A), that it plays a crucial role in apelin receptor internalization but not in apelin binding or in Gαi-protein coupling. Then we built a homology three-dimensional model of the human apelin receptor using the cholecystokinin receptor-1 model as a template, and we subsequently docked K17F into the binding site. We visualized a hydrophobic cavity at the bottom of the binding pocket in which the C-terminal Phe of K17F was embedded by Trp152 in TMIV and Trp259 and Phe255 in TMVI. Using molecular modeling and site-directed mutagenesis studies, we further showed that Phe255 and Trp259 are key residues in triggering receptor internalization without playing a role in apelin binding or in Gαi-protein coupling. These findings bring new insights into apelin receptor activation and show that Phe255 and Trp259, by interacting with the C-terminal Phe of the pyroglutamyl form of apelin 13 (pE13F) or K17F, are crucial for apelin receptor internalization.
Url:
DOI: 10.1074/jbc.M110.127167
PubMed: 20675385
PubMed Central: 2952265
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">By Interacting with the C-terminal Phe of Apelin, Phe<sup>255</sup> and Trp<sup>259</sup> in Helix VI of the Apelin Receptor Are Critical for Internalization<xref ref-type="fn" rid="FN1">*</xref><xref ref-type="fn" rid="FN2"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></title><author><name sortKey="Iturrioz, Xavier" sort="Iturrioz, Xavier" uniqKey="Iturrioz X" first="Xavier" last="Iturrioz">Xavier Iturrioz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gerbier, Romain" sort="Gerbier, Romain" uniqKey="Gerbier R" first="Romain" last="Gerbier">Romain Gerbier</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Université Paris Descarte, Paris FR-75005, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Descarte, Paris FR-75005</wicri:regionArea></affiliation></author><author><name sortKey="Leroux, Vincent" sort="Leroux, Vincent" uniqKey="Leroux V" first="Vincent" last="Leroux">Vincent Leroux</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Alvear Perez, Rodrigo" sort="Alvear Perez, Rodrigo" uniqKey="Alvear Perez R" first="Rodrigo" last="Alvear-Perez">Rodrigo Alvear-Perez</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Llorens Cortes, Catherine" sort="Llorens Cortes, Catherine" uniqKey="Llorens Cortes C" first="Catherine" last="Llorens-Cortes">Catherine Llorens-Cortes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20675385</idno><idno type="pmc">2952265</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952265</idno><idno type="RBID">PMC:2952265</idno><idno type="doi">10.1074/jbc.M110.127167</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000060</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000060</idno><idno type="wicri:Area/Pmc/Curation">000060</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000060</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">By Interacting with the C-terminal Phe of Apelin, Phe<sup>255</sup> and Trp<sup>259</sup> in Helix VI of the Apelin Receptor Are Critical for Internalization<xref ref-type="fn" rid="FN1">*</xref><xref ref-type="fn" rid="FN2"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></title><author><name sortKey="Iturrioz, Xavier" sort="Iturrioz, Xavier" uniqKey="Iturrioz X" first="Xavier" last="Iturrioz">Xavier Iturrioz</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gerbier, Romain" sort="Gerbier, Romain" uniqKey="Gerbier R" first="Romain" last="Gerbier">Romain Gerbier</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Université Paris Descarte, Paris FR-75005, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Paris Descarte, Paris FR-75005</wicri:regionArea></affiliation></author><author><name sortKey="Leroux, Vincent" sort="Leroux, Vincent" uniqKey="Leroux V" first="Vincent" last="Leroux">Vincent Leroux</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Alvear Perez, Rodrigo" sort="Alvear Perez, Rodrigo" uniqKey="Alvear Perez R" first="Rodrigo" last="Alvear-Perez">Rodrigo Alvear-Perez</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Llorens Cortes, Catherine" sort="Llorens Cortes, Catherine" uniqKey="Llorens Cortes C" first="Catherine" last="Llorens-Cortes">Catherine Llorens-Cortes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Apelin is the endogenous ligand of the orphan seven-transmembrane domain (TM) G protein-coupled receptor APJ. Apelin is involved in the regulation of body fluid homeostasis and cardiovascular functions. We previously showed the importance of the C-terminal Phe of apelin 17 (K17F) in the hypotensive activity of this peptide. Here, we show either by deleting the Phe residue (K16P) or by substituting it by an Ala (K17A), that it plays a crucial role in apelin receptor internalization but not in apelin binding or in Gα<sub>i</sub>-protein coupling. Then we built a homology three-dimensional model of the human apelin receptor using the cholecystokinin receptor-1 model as a template, and we subsequently docked K17F into the binding site. We visualized a hydrophobic cavity at the bottom of the binding pocket in which the C-terminal Phe of K17F was embedded by Trp<sup>152</sup> in TMIV and Trp<sup>259</sup> and Phe<sup>255</sup> in TMVI. Using molecular modeling and site-directed mutagenesis studies, we further showed that Phe<sup>255</sup> and Trp<sup>259</sup> are key residues in triggering receptor internalization without playing a role in apelin binding or in Gα<sub>i</sub>-protein coupling. These findings bring new insights into apelin receptor activation and show that Phe<sup>255</sup> and Trp<sup>259</sup>, by interacting with the C-terminal Phe of the pyroglutamyl form of apelin 13 (pE13F) or K17F, are crucial for apelin receptor internalization.</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">J Biol Chem</journal-id><journal-id journal-id-type="hwp">jbc</journal-id><journal-id journal-id-type="pmc">jbc</journal-id><journal-id journal-id-type="publisher-id">JBC</journal-id><journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0021-9258</issn><issn pub-type="epub">1083-351X</issn><publisher><publisher-name>American Society for Biochemistry and Molecular Biology</publisher-name><publisher-loc>9650 Rockville Pike, Bethesda, MD 20814, U.S.A.</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20675385</article-id><article-id pub-id-type="pmc">2952265</article-id><article-id pub-id-type="publisher-id">M110.127167</article-id><article-id pub-id-type="doi">10.1074/jbc.M110.127167</article-id><article-categories><subj-group subj-group-type="heading"><subject>Protein Structure and Folding</subject></subj-group><subj-group><subject>Signal Transduction</subject></subj-group></article-categories><title-group><article-title>By Interacting with the C-terminal Phe of Apelin, Phe<sup>255</sup> and Trp<sup>259</sup> in Helix VI of the Apelin Receptor Are Critical for Internalization<xref ref-type="fn" rid="FN1">*</xref><xref ref-type="fn" rid="FN2"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></article-title><alt-title alt-title-type="short">New Insights into Apelin Receptor Activation</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Iturrioz</surname><given-names>Xavier</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN3"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gerbier</surname><given-names>Romain</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="author-notes" rid="FN3"><sup>1</sup></xref><xref ref-type="author-notes" rid="FN4"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Leroux</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="aff2"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Alvear-Perez</surname><given-names>Rodrigo</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Maigret</surname><given-names>Bernard</given-names></name><xref ref-type="aff" rid="aff2"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Llorens-Cortes</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="corresp" rid="cor1"><sup>3</sup></xref></contrib><aff id="aff1">From<label>‡</label>INSERM, U691, Collège de France, Université Pierre et Marie-Curie Paris 6, Paris FR-75005, France,</aff><aff id="aff2">the<label>¶</label>Orpailleur Group, LORIA UMR CNRS 7503, H. Poincaré University, Nancy FR-54506, France, and</aff><aff id="aff3"><label>§</label>Université Paris Descarte, Paris FR-75005, France</aff></contrib-group><author-notes><corresp id="cor1"><label>3</label> To whom correspondence should be addressed: <addr-line>INSERM U691, Collège de France, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France.</addr-line> Tel.: <phone>33-44-27-16-63</phone>; Fax: <fax>33-44-27-16-67</fax>; E-mail: <email>c.llorens-cortes@college-de-france.fr</email>.</corresp><fn fn-type="equal" id="FN3"><label>1</label><p>Both authors contributed equally to this work.</p></fn><fn fn-type="supported-by" id="FN4"><label>2</label><p>Supported by a grant “Cardiovasculaires-Obésité-Diabète” from Région Ile-de-France.</p></fn></author-notes><pub-date pub-type="ppub"><day>15</day><month>10</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>30</day><month>7</month><year>2010</year></pub-date><volume>285</volume><issue>42</issue><fpage>32627</fpage><lpage>32637</lpage><history><date date-type="received"><day>25</day><month>3</month><year>2010</year></date><date date-type="rev-recd"><day>23</day><month>7</month><year>2010</year></date></history><permissions><copyright-statement>© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.</copyright-statement></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zbc04210032627.pdf"></self-uri><abstract><p>Apelin is the endogenous ligand of the orphan seven-transmembrane domain (TM) G protein-coupled receptor APJ. Apelin is involved in the regulation of body fluid homeostasis and cardiovascular functions. We previously showed the importance of the C-terminal Phe of apelin 17 (K17F) in the hypotensive activity of this peptide. Here, we show either by deleting the Phe residue (K16P) or by substituting it by an Ala (K17A), that it plays a crucial role in apelin receptor internalization but not in apelin binding or in Gα<sub>i</sub>-protein coupling. Then we built a homology three-dimensional model of the human apelin receptor using the cholecystokinin receptor-1 model as a template, and we subsequently docked K17F into the binding site. We visualized a hydrophobic cavity at the bottom of the binding pocket in which the C-terminal Phe of K17F was embedded by Trp<sup>152</sup> in TMIV and Trp<sup>259</sup> and Phe<sup>255</sup> in TMVI. Using molecular modeling and site-directed mutagenesis studies, we further showed that Phe<sup>255</sup> and Trp<sup>259</sup> are key residues in triggering receptor internalization without playing a role in apelin binding or in Gα<sub>i</sub>-protein coupling. These findings bring new insights into apelin receptor activation and show that Phe<sup>255</sup> and Trp<sup>259</sup>, by interacting with the C-terminal Phe of the pyroglutamyl form of apelin 13 (pE13F) or K17F, are crucial for apelin receptor internalization.</p></abstract><kwd-group><kwd>Computer Modeling</kwd><kwd>G Protein-coupled Receptors (GPCR)</kwd><kwd>Peptides</kwd><kwd>Receptor Structure-Function</kwd><kwd>Signal Transduction</kwd><kwd>Site-directed Mutagenesis</kwd><kwd>Internalization</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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