Cooperativity in the Interaction of Synthetic CD40L Mimetics with CD40 and Its Implication in Cell Signaling
CD40 ligand (CD40L) and CD40 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, respectively. Their interaction is crucial for the development of a proper immune response. Intervention on this pathway provides an important ground for new treatments targeting autoimmune di...
Gespeichert in:
Veröffentlicht in: | Biochemistry (Easton) 2007-03, Vol.46 (11), p.3482-3493 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 3493 |
---|---|
container_issue | 11 |
container_start_page | 3482 |
container_title | Biochemistry (Easton) |
container_volume | 46 |
creator | Wieckowski, Sébastien Trouche, Nathalie Chaloin, Olivier Guichard, Gilles Fournel, Sylvie Hoebeke, Johan |
description | CD40 ligand (CD40L) and CD40 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, respectively. Their interaction is crucial for the development of a proper immune response. Intervention on this pathway provides an important ground for new treatments targeting autoimmune diseases or helping to fight infection and cancer. We have recently reported on the structure-based design of synthetic molecules with C 3 symmetry, named mini-CD40Ls, that can effectively mimic homotrimeric soluble CD40L. Here we show that substitution of a d-prolyl residue for the glycyl within the Lys-Gly-Tyr-Tyr CD40-binding motif leads to a complete loss of cooperativity in the interaction of the mimetic with its cognate receptor as assessed by surface plasmon resonance experiments. The ability of the modified mini-CD40L to induce apoptosis on both human and murine lymphoma cells was not affected by this mutation. However, it was unable to induce the NF-κB pathway in the mouse D1 dendritic cell line, which is essential for its complete maturation, but still activated production of IL-12 p40 mRNA. These differential effects might be partly explained by the change in rigidity of the CD40 recognition element. In this study, we not only point out the consequences of the abrogation of the cooperative property in a ligand−receptor interaction on downstream cellular events but also demonstrate the usefulness of synthetic multivalent ligands in dissecting the complex mechanisms implicated in the signalosome. |
doi_str_mv | 10.1021/bi602434a |
format | Article |
fullrecord | <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_00165292v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>20497688</sourcerecordid><originalsourceid>FETCH-LOGICAL-a416t-7a5f0fa15869a538b183549b8b126be13e1b5933787e9f78da72881dd38e6ddd3</originalsourceid><addsrcrecordid>eNqFkUtvEzEUhS1ERUNhwR9A3lCpiyl-P5bV0JKgQSAlrC3PjKdxmRmHsVPIv8dponSDxOr6Hn8-98oHgHcYXWNE8MfaC0QYZfYFmGFOUMG05i_BDCEkCqIFOgevY3zILUOSvQLnWFKshdYz0JchbNxkk3_0aQf9CNPawcWYstYkH0YYOrjcjVlNvoHlJ4Yq-NUP-y7C3z6tnzRoxxYuUoSLYdP7xj69zGal63u49Pej7f14_wacdbaP7u2xXoAfd7ercl5U3z4vypuqsAyLVEjLO9RZzJXQllNVY0U503U-EFE7TB2uuaZUKul0J1VrJVEKty1VTrS5XICrg-_a9mYz-cFOOxOsN_Obyuw1hLDgRJNHnNnLA7uZwq-ti8kMPjZ5bTu6sI1GIiI41vK_IEFMS6HU8_RmCjFOrjutgJHZ52VOeWX2_dF0Ww-ufSaPAWWgOAA-JvfndG-nn0ZIKrlZfV-ais7Vl3JFzZ7_cOBtE81D2E755-M_Bv8FwnaoiA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20497688</pqid></control><display><type>article</type><title>Cooperativity in the Interaction of Synthetic CD40L Mimetics with CD40 and Its Implication in Cell Signaling</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Wieckowski, Sébastien ; Trouche, Nathalie ; Chaloin, Olivier ; Guichard, Gilles ; Fournel, Sylvie ; Hoebeke, Johan</creator><creatorcontrib>Wieckowski, Sébastien ; Trouche, Nathalie ; Chaloin, Olivier ; Guichard, Gilles ; Fournel, Sylvie ; Hoebeke, Johan</creatorcontrib><description>CD40 ligand (CD40L) and CD40 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, respectively. Their interaction is crucial for the development of a proper immune response. Intervention on this pathway provides an important ground for new treatments targeting autoimmune diseases or helping to fight infection and cancer. We have recently reported on the structure-based design of synthetic molecules with C 3 symmetry, named mini-CD40Ls, that can effectively mimic homotrimeric soluble CD40L. Here we show that substitution of a d-prolyl residue for the glycyl within the Lys-Gly-Tyr-Tyr CD40-binding motif leads to a complete loss of cooperativity in the interaction of the mimetic with its cognate receptor as assessed by surface plasmon resonance experiments. The ability of the modified mini-CD40L to induce apoptosis on both human and murine lymphoma cells was not affected by this mutation. However, it was unable to induce the NF-κB pathway in the mouse D1 dendritic cell line, which is essential for its complete maturation, but still activated production of IL-12 p40 mRNA. These differential effects might be partly explained by the change in rigidity of the CD40 recognition element. In this study, we not only point out the consequences of the abrogation of the cooperative property in a ligand−receptor interaction on downstream cellular events but also demonstrate the usefulness of synthetic multivalent ligands in dissecting the complex mechanisms implicated in the signalosome.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi602434a</identifier><identifier>PMID: 17319699</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Antigens, CD40 ; Apoptosis ; Biochemistry, Molecular Biology ; CD40 Antigens - genetics ; CD40 Antigens - metabolism ; CD40 Ligand ; CD40 Ligand - genetics ; CD40 Ligand - metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Proliferation - drug effects ; Dendritic Cells ; Dendritic Cells - immunology ; Glycine ; Glycine - physiology ; Humans ; Jurkat Cells ; Life Sciences ; Mice ; Proline ; Proline - physiology ; Signal Transduction ; Surface Plasmon Resonance</subject><ispartof>Biochemistry (Easton), 2007-03, Vol.46 (11), p.3482-3493</ispartof><rights>Copyright © 2007 American Chemical Society</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a416t-7a5f0fa15869a538b183549b8b126be13e1b5933787e9f78da72881dd38e6ddd3</citedby><cites>FETCH-LOGICAL-a416t-7a5f0fa15869a538b183549b8b126be13e1b5933787e9f78da72881dd38e6ddd3</cites><orcidid>0000-0002-2584-7502 ; 0000-0003-3045-4452 ; 0000-0003-3583-6548</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bi602434a$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi602434a$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17319699$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00165292$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Wieckowski, Sébastien</creatorcontrib><creatorcontrib>Trouche, Nathalie</creatorcontrib><creatorcontrib>Chaloin, Olivier</creatorcontrib><creatorcontrib>Guichard, Gilles</creatorcontrib><creatorcontrib>Fournel, Sylvie</creatorcontrib><creatorcontrib>Hoebeke, Johan</creatorcontrib><title>Cooperativity in the Interaction of Synthetic CD40L Mimetics with CD40 and Its Implication in Cell Signaling</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>CD40 ligand (CD40L) and CD40 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, respectively. Their interaction is crucial for the development of a proper immune response. Intervention on this pathway provides an important ground for new treatments targeting autoimmune diseases or helping to fight infection and cancer. We have recently reported on the structure-based design of synthetic molecules with C 3 symmetry, named mini-CD40Ls, that can effectively mimic homotrimeric soluble CD40L. Here we show that substitution of a d-prolyl residue for the glycyl within the Lys-Gly-Tyr-Tyr CD40-binding motif leads to a complete loss of cooperativity in the interaction of the mimetic with its cognate receptor as assessed by surface plasmon resonance experiments. The ability of the modified mini-CD40L to induce apoptosis on both human and murine lymphoma cells was not affected by this mutation. However, it was unable to induce the NF-κB pathway in the mouse D1 dendritic cell line, which is essential for its complete maturation, but still activated production of IL-12 p40 mRNA. These differential effects might be partly explained by the change in rigidity of the CD40 recognition element. In this study, we not only point out the consequences of the abrogation of the cooperative property in a ligand−receptor interaction on downstream cellular events but also demonstrate the usefulness of synthetic multivalent ligands in dissecting the complex mechanisms implicated in the signalosome.</description><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Antigens, CD40</subject><subject>Apoptosis</subject><subject>Biochemistry, Molecular Biology</subject><subject>CD40 Antigens - genetics</subject><subject>CD40 Antigens - metabolism</subject><subject>CD40 Ligand</subject><subject>CD40 Ligand - genetics</subject><subject>CD40 Ligand - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Dendritic Cells</subject><subject>Dendritic Cells - immunology</subject><subject>Glycine</subject><subject>Glycine - physiology</subject><subject>Humans</subject><subject>Jurkat Cells</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Proline</subject><subject>Proline - physiology</subject><subject>Signal Transduction</subject><subject>Surface Plasmon Resonance</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtvEzEUhS1ERUNhwR9A3lCpiyl-P5bV0JKgQSAlrC3PjKdxmRmHsVPIv8dponSDxOr6Hn8-98oHgHcYXWNE8MfaC0QYZfYFmGFOUMG05i_BDCEkCqIFOgevY3zILUOSvQLnWFKshdYz0JchbNxkk3_0aQf9CNPawcWYstYkH0YYOrjcjVlNvoHlJ4Yq-NUP-y7C3z6tnzRoxxYuUoSLYdP7xj69zGal63u49Pej7f14_wacdbaP7u2xXoAfd7ercl5U3z4vypuqsAyLVEjLO9RZzJXQllNVY0U503U-EFE7TB2uuaZUKul0J1VrJVEKty1VTrS5XICrg-_a9mYz-cFOOxOsN_Obyuw1hLDgRJNHnNnLA7uZwq-ti8kMPjZ5bTu6sI1GIiI41vK_IEFMS6HU8_RmCjFOrjutgJHZ52VOeWX2_dF0Ww-ufSaPAWWgOAA-JvfndG-nn0ZIKrlZfV-ais7Vl3JFzZ7_cOBtE81D2E755-M_Bv8FwnaoiA</recordid><startdate>20070320</startdate><enddate>20070320</enddate><creator>Wieckowski, Sébastien</creator><creator>Trouche, Nathalie</creator><creator>Chaloin, Olivier</creator><creator>Guichard, Gilles</creator><creator>Fournel, Sylvie</creator><creator>Hoebeke, Johan</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2584-7502</orcidid><orcidid>https://orcid.org/0000-0003-3045-4452</orcidid><orcidid>https://orcid.org/0000-0003-3583-6548</orcidid></search><sort><creationdate>20070320</creationdate><title>Cooperativity in the Interaction of Synthetic CD40L Mimetics with CD40 and Its Implication in Cell Signaling</title><author>Wieckowski, Sébastien ; Trouche, Nathalie ; Chaloin, Olivier ; Guichard, Gilles ; Fournel, Sylvie ; Hoebeke, Johan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a416t-7a5f0fa15869a538b183549b8b126be13e1b5933787e9f78da72881dd38e6ddd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Antigens, CD40</topic><topic>Apoptosis</topic><topic>Biochemistry, Molecular Biology</topic><topic>CD40 Antigens - genetics</topic><topic>CD40 Antigens - metabolism</topic><topic>CD40 Ligand</topic><topic>CD40 Ligand - genetics</topic><topic>CD40 Ligand - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Dendritic Cells</topic><topic>Dendritic Cells - immunology</topic><topic>Glycine</topic><topic>Glycine - physiology</topic><topic>Humans</topic><topic>Jurkat Cells</topic><topic>Life Sciences</topic><topic>Mice</topic><topic>Proline</topic><topic>Proline - physiology</topic><topic>Signal Transduction</topic><topic>Surface Plasmon Resonance</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wieckowski, Sébastien</creatorcontrib><creatorcontrib>Trouche, Nathalie</creatorcontrib><creatorcontrib>Chaloin, Olivier</creatorcontrib><creatorcontrib>Guichard, Gilles</creatorcontrib><creatorcontrib>Fournel, Sylvie</creatorcontrib><creatorcontrib>Hoebeke, Johan</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wieckowski, Sébastien</au><au>Trouche, Nathalie</au><au>Chaloin, Olivier</au><au>Guichard, Gilles</au><au>Fournel, Sylvie</au><au>Hoebeke, Johan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cooperativity in the Interaction of Synthetic CD40L Mimetics with CD40 and Its Implication in Cell Signaling</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2007-03-20</date><risdate>2007</risdate><volume>46</volume><issue>11</issue><spage>3482</spage><epage>3493</epage><pages>3482-3493</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>CD40 ligand (CD40L) and CD40 are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, respectively. Their interaction is crucial for the development of a proper immune response. Intervention on this pathway provides an important ground for new treatments targeting autoimmune diseases or helping to fight infection and cancer. We have recently reported on the structure-based design of synthetic molecules with C 3 symmetry, named mini-CD40Ls, that can effectively mimic homotrimeric soluble CD40L. Here we show that substitution of a d-prolyl residue for the glycyl within the Lys-Gly-Tyr-Tyr CD40-binding motif leads to a complete loss of cooperativity in the interaction of the mimetic with its cognate receptor as assessed by surface plasmon resonance experiments. The ability of the modified mini-CD40L to induce apoptosis on both human and murine lymphoma cells was not affected by this mutation. However, it was unable to induce the NF-κB pathway in the mouse D1 dendritic cell line, which is essential for its complete maturation, but still activated production of IL-12 p40 mRNA. These differential effects might be partly explained by the change in rigidity of the CD40 recognition element. In this study, we not only point out the consequences of the abrogation of the cooperative property in a ligand−receptor interaction on downstream cellular events but also demonstrate the usefulness of synthetic multivalent ligands in dissecting the complex mechanisms implicated in the signalosome.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>17319699</pmid><doi>10.1021/bi602434a</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-2584-7502</orcidid><orcidid>https://orcid.org/0000-0003-3045-4452</orcidid><orcidid>https://orcid.org/0000-0003-3583-6548</orcidid></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0006-2960 |
ispartof | Biochemistry (Easton), 2007-03, Vol.46 (11), p.3482-3493 |
issn | 0006-2960 1520-4995 |
language | eng |
recordid | cdi_hal_primary_oai_HAL_hal_00165292v1 |
source | MEDLINE; American Chemical Society Journals |
subjects | Amino Acid Sequence Amino Acid Substitution Animals Antigens, CD40 Apoptosis Biochemistry, Molecular Biology CD40 Antigens - genetics CD40 Antigens - metabolism CD40 Ligand CD40 Ligand - genetics CD40 Ligand - metabolism Cell Line, Tumor Cell Proliferation Cell Proliferation - drug effects Dendritic Cells Dendritic Cells - immunology Glycine Glycine - physiology Humans Jurkat Cells Life Sciences Mice Proline Proline - physiology Signal Transduction Surface Plasmon Resonance |
title | Cooperativity in the Interaction of Synthetic CD40L Mimetics with CD40 and Its Implication in Cell Signaling |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T01%3A39%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cooperativity%20in%20the%20Interaction%20of%20Synthetic%20CD40L%20Mimetics%20with%20CD40%20and%20Its%20Implication%20in%20Cell%20Signaling&rft.jtitle=Biochemistry%20(Easton)&rft.au=Wieckowski,%20S%C3%A9bastien&rft.date=2007-03-20&rft.volume=46&rft.issue=11&rft.spage=3482&rft.epage=3493&rft.pages=3482-3493&rft.issn=0006-2960&rft.eissn=1520-4995&rft_id=info:doi/10.1021/bi602434a&rft_dat=%3Cproquest_hal_p%3E20497688%3C/proquest_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=20497688&rft_id=info:pmid/17319699&rfr_iscdi=true |