Intrinsic disorder and fuzzy interactions drive multiple functions of HMGB1

HMGB1, a multitasking protein, is scrutinized here through the lens of the 'fuzzy interactions' driven by its intrinsically disordered regions (IDRs). Although the multiple intracellular and extracellular functions of this protein have been studied for decades, viewing HMGB1 as fuzzy and dynamic provides a novel perspective. Recent breakthroughs emphasize the crucial role of its IDRs, especially the acidic C-terminal tail, in mediating dynamic multivalent interactions. This fuzziness enables HMGB1 to modulate DNA and chromatin binding, to chaperone other proteins such as p53, and to tune inflammatory signals via receptors such as TLR4 and CXCR4. Understanding the fuzzy nature of HMGB1 unlocks new therapeutic strategies targeting both its structured and unstructured regions to tackle a range of diseases.