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| Gene | [HMGB1](/genes/hmgb1) |
| UniProt |
P09429 |
| PDB |
2YRQ, 1CKT |
| Mol. Weight |
~25 kDa (215 aa) |
| Localization |
Nucleus, cytoplasm, extracellular (secreted DAMP) |
| Family |
HMG-box superfamily |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), Stroke |
HMGB1 (High Mobility Group Box 1) is a 25 kDa nuclear protein encoded by the HMGB1 gene that serves dual roles as a chromatin architectural factor and an extracellular danger-associated molecular pattern (DAMP). HMGB1 is one of the most abundant non-histone nuclear proteins, present at approximately 10^6 molecules per cell. Its release from damaged neurons activates innate immune receptors — principally RAGE and TLR4 — on microglia and astrocytes, making it a central amplifier of neuroinflammation in neurodegenerative diseases.
¶ Domain Organization
HMGB1 contains three distinct functional domains arranged in a linear topology:
- A-box (residues 1-79): L-shaped HMG box domain with three alpha-helices. Binds DNA minor groove and bends DNA ~90°. The isolated A-box acts as a competitive antagonist of full-length HMGB1, making it therapeutically relevant.
- B-box (residues 89-163): Second HMG box domain responsible for pro-inflammatory cytokine-inducing activity. The minimal cytokine-inducing domain maps to residues 89-108 (B-box peptide). This domain contains the TLR4-binding epitope.
- Acidic C-terminal tail (residues 186-215): Thirty consecutive aspartate and glutamate residues. Regulates DNA binding affinity and specificity by intramolecular interaction with the HMG boxes.
The linker region between the two HMG boxes (residues 80-88) and between the B-box and acidic tail confers flexibility essential for DNA bending.
Three cysteine residues (C23, C45, C106) serve as a molecular redox switch:
- C23 and C45: Located in the A-box; can form an intramolecular disulfide bond
- C106: Located in the B-box; its oxidation state determines inflammatory vs. chemotactic activity
- The redox state of these cysteines dictates which receptors HMGB1 engages:
- All-thiol → CXCR4 (chemotaxis)
- C23-C45 disulfide, C106-thiol → TLR4 (inflammation)
- All-sulfonyl → inactive (resolution)
Available structures (PDB: 2YRQ for A-box, 1CKT for B-box) reveal:
- Each HMG box adopts an L-shaped fold with helices I and II forming one arm and helix III the other
- DNA intercalation occurs through conserved phenylalanine residues (F38 in A-box, F103 in B-box)
- The acidic tail is intrinsically disordered and not resolved in crystal structures
¶ Function and Signaling
- Chromatin remodeling: HMGB1 binds nucleosomes at the dyad axis and linker DNA, loosening chromatin and facilitating transcription factor access
- Transcription enhancement: Directly recruits and stabilizes binding of p53, NF-κB, glucocorticoid receptors, and estrogen receptors
- DNA repair coordination: HMGB1 recognizes distorted DNA structures (UV damage, cisplatin adducts, abasic sites) and recruits repair machinery
- Chromosome segregation: Required for proper mitotic chromosome condensation and segregation
When released extracellularly, HMGB1 activates multiple receptor pathways:
RAGE Pathway:
- HMGB1 binds RAGE V-domain with nanomolar affinity
- Activates Ras/MAPK, PI3K/AKT, and NF-κB pathways
- Upregulates pro-inflammatory cytokines (TNF-α, IL-1β, IL-6)
- Sustained RAGE activation promotes amyloid-β neuronal uptake and toxicity
TLR4/MD-2 Pathway:
- Disulfide-HMGB1 binds the TLR4/MD-2 receptor complex
- Activates MyD88-dependent signaling (rapid NF-κB activation)
- Activates TRIF-dependent signaling (type I interferon production)
- Triggers NLRP3 inflammasome priming
CXCR4 Pathway:
- All-thiol HMGB1 forms a heterocomplex with CXCL12
- HMGB1/CXCL12 binds CXCR4 with enhanced affinity
- Promotes immune cell chemotaxis and microglial migration toward injury sites
HMGB1 release from cells occurs through multiple routes:
- Passive release: Necrotic cell death releases nuclear HMGB1 en masse
- Active secretion: Activated microglia, macrophages, and dendritic cells actively secrete HMGB1 via:
- Hyperacetylation of nuclear localization signals (NLS1 and NLS2)
- JAK/STAT1-dependent phosphorylation
- Lysosomal exocytosis pathway
- Pyroptotic release: NLRP3 inflammasome activation and gasdermin D pore formation release HMGB1
- NETosis: Neutrophil extracellular trap formation releases chromatin-bound HMGB1
HMGB1 protein forms pathological interactions in AD:
- Directly binds amyloid-β peptide (Aβ42 > Aβ40), forming HMGB1-Aβ complexes that resist microglial phagocytosis
- HMGB1-Aβ complexes activate microglia more potently than Aβ alone, creating a vicious inflammatory cycle
- Immunodepletion of HMGB1 from AD brain extracts reduces microglial activation by ~60%
- HMGB1 colocalizes with amyloid plaques in AD brain tissue
- Promotes tau hyperphosphorylation through RAGE-GSK3β-tau axis
In PD:
- α-Synuclein aggregates induce HMGB1 release from dopaminergic neurons
- Released HMGB1 activates microglial TLR4, sustaining chronic neuroinflammation in the substantia nigra
- Anti-HMGB1 antibodies protect against MPTP-induced dopaminergic neuron loss in mice
- HMGB1 directly interacts with α-synuclein, promoting its aggregation
In amyotrophic lateral sclerosis:
- Motor neuron degeneration releases HMGB1 into the spinal cord microenvironment
- TDP-43 pathology promotes HMGB1 nuclear-to-cytoplasmic translocation
- Spinal cord microglia and astrocytes upregulate RAGE and TLR4 in ALS
- Serum HMGB1 levels correlate with disease progression rate and survival
| Partner |
Interaction |
Function |
| Amyloid-β |
Direct binding |
Inflammatory complex formation |
| RAGE |
Receptor-ligand |
NF-κB activation |
| TLR4/MD-2 |
Receptor-ligand |
Innate immune activation |
| α-Synuclein |
Direct binding |
Aggregation promotion |
| p53 |
Transcriptional cooperation |
DNA damage response |
| CXCL12 |
Heterocomplex |
Chemotaxis enhancement |
| Nucleosomes |
Chromatin interaction |
Gene regulation |
| Beclin-1 |
Direct binding |
Autophagy regulation |