We are pleased to announce the publication of a new scientific insight by Professor Marco E. Bianchi, Co-founder and Part-owner of HMGBiotech, regarding the Intrinsic disorder and Fuzzy interactions drive multiple functions of HMGB1.
This study underscores the central role of intrinsically disordered regions (IDRs) and fuzzy interactions in shaping the molecular plasticity and functional repertoire of HMGB1 across different biological contexts.
HMGB1 essential for chromatin organization
High Mobility Group Protein 1 has long been recognized as a multitasking protein, core for chromatin organization in the nucleus and for triggering inflammation when released extracellularly.
What this new perspective brings to light is that HMGB1’s versatility is not merely due to its redox states or structured DNA-binding boxes (A and B), but fundamentally tied to its conformational flexibility and disordered regions—specifically, the acidic C-terminal tail.
- In HMGB1 fuzzy interactions allow the protein to remain structurally dynamic even while engaged in binding.
- The acidic IDR enables HMGB1 to interact with a wide variety of ligands and receptors, acting alternately as an autoinhibitory module, a molecular chaperone, or a functional switch.
The acidic tail of HMGB1, composed of repetitive negatively charged residues, is highly conserved across species. Its evolutionary preservation points to a fundamental biological role, now attributed to its contribution to fuzzy complex formation.
- Intracellularly, the acidic IDR regulates DNA binding, histone interaction, and p53 function, acting as an autoinhibitory and chaperoning module.
- Extracellularly, it contributes to receptor engagement (TLR2/4, RAGE, CXCR4), alongside redox-dependent mechanisms.
The findings of the study reinforce the critical translational potential of HMGB1, whose disordered nature enables functional versatility across diverse pathophysiological contexts—from cancer and infection to sterile inflammation. The ability to modulate its activity at the level of disorder-driven interactions could revolutionize intervention strategies.
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