The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12
Abstract Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protei...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45505-7 |
| _version_ | 1827326953170927616 |
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| author | Malisa Vittoria Mantonico Federica De Leo Giacomo Quilici Liam Sean Colley Francesco De Marchis Massimo Crippa Rosanna Mezzapelle Tim Schulte Chiara Zucchelli Chiara Pastorello Camilla Carmeno Francesca Caprioglio Stefano Ricagno Gabriele Giachin Michela Ghitti Marco Emilio Bianchi Giovanna Musco |
| author_facet | Malisa Vittoria Mantonico Federica De Leo Giacomo Quilici Liam Sean Colley Francesco De Marchis Massimo Crippa Rosanna Mezzapelle Tim Schulte Chiara Zucchelli Chiara Pastorello Camilla Carmeno Francesca Caprioglio Stefano Ricagno Gabriele Giachin Michela Ghitti Marco Emilio Bianchi Giovanna Musco |
| author_sort | Malisa Vittoria Mantonico |
| collection | DOAJ |
| description | Abstract Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. The molecular details of complex formation were still elusive. Here we show by an integrated structural approach that frHMGB1•CXCL12 is a fuzzy heterocomplex. Unlike previous assumptions, frHMGB1 and CXCL12 form a dynamic equimolar assembly, with structured and unstructured frHMGB1 regions recognizing the CXCL12 dimerization surface. We uncover an unexpected role of the acidic intrinsically disordered region (IDR) of HMGB1 in heterocomplex formation and its binding to CXCR4 on the cell surface. Our work shows that the interaction of frHMGB1 with CXCL12 diverges from the classical rigid heterophilic chemokines dimerization. Simultaneous interference with multiple interactions within frHMGB1•CXCL12 might offer pharmacological strategies against inflammatory conditions. |
| first_indexed | 2024-03-07T14:52:56Z |
| format | Article |
| id | doaj.art-d054899c802941a79cd558a8f7c91f5a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:56Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d054899c802941a79cd558a8f7c91f5a2024-03-05T19:36:14ZengNature PortfolioNature Communications2041-17232024-02-0115111810.1038/s41467-024-45505-7The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12Malisa Vittoria Mantonico0Federica De Leo1Giacomo Quilici2Liam Sean Colley3Francesco De Marchis4Massimo Crippa5Rosanna Mezzapelle6Tim Schulte7Chiara Zucchelli8Chiara Pastorello9Camilla Carmeno10Francesca Caprioglio11Stefano Ricagno12Gabriele Giachin13Michela Ghitti14Marco Emilio Bianchi15Giovanna Musco16Biomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleHMGBiotech S.r.l.School of Medicine, Università Vita e Salute-San RaffaeleChromatin Dynamics Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleSchool of Medicine, Università Vita e Salute-San RaffaeleInstitute of Molecular and Translational Cardiology, IRCCS Policlinico San DonatoBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleSchool of Medicine, Università Vita e Salute-San RaffaeleInstitute of Molecular and Translational Cardiology, IRCCS Policlinico San DonatoDepartment of Chemical Sciences (DiSC), University of PaduaBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleSchool of Medicine, Università Vita e Salute-San RaffaeleBiomolecular NMR Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San RaffaeleAbstract Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. The molecular details of complex formation were still elusive. Here we show by an integrated structural approach that frHMGB1•CXCL12 is a fuzzy heterocomplex. Unlike previous assumptions, frHMGB1 and CXCL12 form a dynamic equimolar assembly, with structured and unstructured frHMGB1 regions recognizing the CXCL12 dimerization surface. We uncover an unexpected role of the acidic intrinsically disordered region (IDR) of HMGB1 in heterocomplex formation and its binding to CXCR4 on the cell surface. Our work shows that the interaction of frHMGB1 with CXCL12 diverges from the classical rigid heterophilic chemokines dimerization. Simultaneous interference with multiple interactions within frHMGB1•CXCL12 might offer pharmacological strategies against inflammatory conditions.https://doi.org/10.1038/s41467-024-45505-7 |
| spellingShingle | Malisa Vittoria Mantonico Federica De Leo Giacomo Quilici Liam Sean Colley Francesco De Marchis Massimo Crippa Rosanna Mezzapelle Tim Schulte Chiara Zucchelli Chiara Pastorello Camilla Carmeno Francesca Caprioglio Stefano Ricagno Gabriele Giachin Michela Ghitti Marco Emilio Bianchi Giovanna Musco The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 Nature Communications |
| title | The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 |
| title_full | The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 |
| title_fullStr | The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 |
| title_full_unstemmed | The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 |
| title_short | The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 |
| title_sort | acidic intrinsically disordered region of the inflammatory mediator hmgb1 mediates fuzzy interactions with cxcl12 |
| url | https://doi.org/10.1038/s41467-024-45505-7 |
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