Dr. Giovanna Musco - The fuzzy logic of the alarmin HMGB1: how disorder drives the interaction with the chemokine CXCL12 - IPBS-Toulouse, Seminar Room

Giovanna Musco

Biomolecular NMR San Raffaele Hospital, Milan, Italy

The fuzzy logic of the alarmin HMGB1: how disorder drives the interaction with the chemokine CXCL12

Chemokines heterodimers activate or dampen their cognate receptors during inflammation. CXCL12 chemokine forms with the alarmin HMGB1 (High Mobility Group B1) a crucial heterocomplex (HMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. As such HMGB1•CXCL12 has become a pharmacological target for inflammation related malignancies (e.g. cancer) (1). However, the molecular details of complex formation were still elusive. By an integrated structural approach (NMR, ITC, MST, AUC, SAXS) we show that HMGB1•CXCL12 is a fuzzy heterocomplex, the first reported for chemokines (2). Unlike previous assumptions, HMGB1 and CXCL12 form a dynamic equimolar assembly, with structured and unstructured HMGB1 regions recognizing the CXCL12 dimerization surface.
Our findings shift the understanding of this complex from the traditional rigid heterophilic chemokine dimerization mechanism to a "fuzzy" model (3), where HMGB1’s acidic intrinsically disordered region (IDR) plays a crucial role in complex assembly and in binding to CXCR4 on malignant mesothelioma cells surface. Simultaneous interference with multiple interactions within HMGB1•CXCL12 might offer novel pharmacological strategies against inflammatory conditions.

Selected references

• De Leo et al. Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment EMBO Rep (2019) 20: e47788
• Mantonico et al. The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12 Nat Commun (2024) 15: 1201
• M. Ghitti et al. Intrinsic disorder and fuzzy interactions drive multiple functions of HMGB1 Trends Biochem Sci (2025) 50(10):906-918