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The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12

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  • Malisa Vittoria Mantonico

    (IRCCS Ospedale San Raffaele
    Università Vita e Salute-San Raffaele)

  • Federica Leo

    (IRCCS Ospedale San Raffaele
    Fondazione AIRC per la Ricerca sul Cancro ETS)

  • Giacomo Quilici

    (IRCCS Ospedale San Raffaele)

  • Liam Sean Colley

    (HMGBiotech S.r.l.
    Università Milano‐Bicocca)

  • Francesco Marchis

    (Università Vita e Salute-San Raffaele
    IRCCS Ospedale San Raffaele)

  • Massimo Crippa

    (IRCCS Ospedale San Raffaele)

  • Rosanna Mezzapelle

    (Università Vita e Salute-San Raffaele
    IRCCS Ospedale San Raffaele)

  • Tim Schulte

    (IRCCS Policlinico San Donato)

  • Chiara Zucchelli

    (IRCCS Ospedale San Raffaele)

  • Chiara Pastorello

    (IRCCS Ospedale San Raffaele)

  • Camilla Carmeno

    (IRCCS Ospedale San Raffaele)

  • Francesca Caprioglio

    (Università Vita e Salute-San Raffaele
    IRCCS Ospedale San Raffaele)

  • Stefano Ricagno

    (IRCCS Policlinico San Donato
    Università degli Studi di Milano)

  • Gabriele Giachin

    (University of Padua)

  • Michela Ghitti

    (IRCCS Ospedale San Raffaele)

  • Marco Emilio Bianchi

    (Università Vita e Salute-San Raffaele
    IRCCS Ospedale San Raffaele)

  • Giovanna Musco

    (IRCCS Ospedale San Raffaele)

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.

Suggested Citation

  • Malisa Vittoria Mantonico & Federica Leo & Giacomo Quilici & Liam Sean Colley & Francesco Marchis & Massimo Crippa & Rosanna Mezzapelle & Tim Schulte & Chiara Zucchelli & Chiara Pastorello & Camilla C, 2024. "The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45505-7
    DOI: 10.1038/s41467-024-45505-7
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    1. Alessandro Borgia & Madeleine B. Borgia & Katrine Bugge & Vera M. Kissling & Pétur O. Heidarsson & Catarina B. Fernandes & Andrea Sottini & Andrea Soranno & Karin J. Buholzer & Daniel Nettels & Birthe, 2018. "Extreme disorder in an ultrahigh-affinity protein complex," Nature, Nature, vol. 555(7694), pages 61-66, March.
    2. Paola Scaffidi & Tom Misteli & Marco E. Bianchi, 2002. "Release of chromatin protein HMGB1 by necrotic cells triggers inflammation," Nature, Nature, vol. 418(6894), pages 191-195, July.
    3. Martin A. Mensah & Henri Niskanen & Alexandre P. Magalhaes & Shaon Basu & Martin Kircher & Henrike L. Sczakiel & Alisa M. V. Reiter & Jonas Elsner & Peter Meinecke & Saskia Biskup & Brian H. Y. Chung , 2023. "Aberrant phase separation and nucleolar dysfunction in rare genetic diseases," Nature, Nature, vol. 614(7948), pages 564-571, February.
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