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

Malisa Vittoria Mantonico, Federica Leo, Giacomo Quilici, Liam Sean Colley, Francesco Marchis, Massimo Crippa, Rosanna Mezzapelle, Tim Schulte, Chiara Zucchelli, Chiara Pastorello, Camilla Carmeno, Francesca Caprioglio, Stefano Ricagno, Gabriele Giachin, Michela Ghitti (), Marco Emilio Bianchi and Giovanna Musco ()
Additional contact information
Malisa Vittoria Mantonico: IRCCS Ospedale San Raffaele
Federica Leo: IRCCS Ospedale San Raffaele
Giacomo Quilici: IRCCS Ospedale San Raffaele
Liam Sean Colley: HMGBiotech S.r.l.
Francesco Marchis: Università Vita e Salute-San Raffaele
Massimo Crippa: IRCCS Ospedale San Raffaele
Rosanna Mezzapelle: Università Vita e Salute-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
Stefano Ricagno: IRCCS Policlinico San Donato
Gabriele Giachin: University of Padua
Michela Ghitti: IRCCS Ospedale San Raffaele
Marco Emilio Bianchi: Università Vita e Salute-San Raffaele
Giovanna Musco: IRCCS Ospedale San Raffaele

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45505-7

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