HMGB1 Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HMGB1 Protein</th>
</tr>
<tr> [@paudel2018]
<td class="label">Gene</td> [@lotze2005]
<td>[HMGB1](/genes/hmgb1)</td> [@andersson2011]
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P09429" target="_blank">P09429</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2YRQ" target="_blank">2YRQ</a>, <a href="https://www.rcsb.org/structure/1CKT" target="_blank">1CKT</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~25 kDa (215 aa)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Nucleus, cytoplasm, extracellular (secreted DAMP)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>HMG-box superfamily</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als), Stroke</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">604 edges</a></td>
</tr>
</table>
HMGB1 Protein
Overview
HMGB1 (High Mobility Group Box 1) is a 25 kDa nuclear protein encoded by the [HMGB1](/genes/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](/entities/neurons) activates innate immune receptors — principally [RAGE](/genes/rage) and [TLR4](/genes/tlr4) — on [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/cell-types/astrocytes), making it a central amplifier of [neuroinflammation](/mechanisms/neuroinflammation) in neurodegenerative diseases.
Structure
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](/entities/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.
Critical Cysteine Residues
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)
Crystal Structure
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
Intranuclear Functions
- 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](/genes/tp53), [NF-κB](/genes/nfkb1), 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
DAMP Signaling Cascade
When released extracellularly, HMGB1 activates multiple receptor pathways:
[RAGE](/entities/rage-receptor) Pathway:
- HMGB1 binds RAGE V-domain with nanomolar affinity
- Activates Ras/MAPK, [PI3K](/genes/pik3ca)/[AKT](/genes/akt1), and [NF-κB](/genes/nfkb1) pathways
- Upregulates pro-inflammatory cytokines ([TNF-α](/genes/tnf), [IL-1β](/genes/il1b), [IL-6](/genes/il6))
- Sustained RAGE activation promotes [amyloid-β](/proteins/amyloid-beta-protein) neuronal uptake and toxicity
TLR4/MD-2 Pathway:
- Disulfide-HMGB1 binds the TLR4/MD-2 receptor complex
- Activates [MyD88](/genes/myd88)-dependent signaling (rapid [NF-κB](/entities/nf-kb) activation)
- Activates TRIF-dependent signaling (type I interferon production)
- Triggers [NLRP3](/genes/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
Secretion Mechanisms
HMGB1 release from cells occurs through multiple routes:
- Passive release: Necrotic cell death releases nuclear HMGB1 en masse
- Active secretion: Activated [microglia](/cell-types/microglia-neuroinflammation), 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](/genes/nlrp3) inflammasome activation and gasdermin D pore formation release HMGB1
- NETosis: Neutrophil extracellular trap formation releases chromatin-bound HMGB1
Role in Neurodegenerative Diseases
Alzheimer's Disease
HMGB1 protein forms pathological interactions in [AD](/diseases/alzheimers-disease):
- Directly binds [amyloid-β](/proteins/amyloid-beta-protein) peptide ([Aβ42](/proteins/amyloid-beta) > 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](/mechanisms/amyloid-pathology) in AD brain tissue
- Promotes [tau](/proteins/tau) hyperphosphorylation through RAGE-GSK3β-[tau](/proteins/tau) axis
Parkinson's Disease
In [PD](/diseases/parkinsons-disease):
- [α-Synuclein](/proteins/alpha-synuclein) aggregates induce HMGB1 release from dopaminergic neurons
- Released HMGB1 activates microglial TLR4, sustaining chronic neuroinflammation in the [substantia nigra](/brain-regions/substantia-nigra)
- Anti-HMGB1 antibodies protect against MPTP-induced dopaminergic neuron loss in mice
- HMGB1 directly interacts with α-synuclein, promoting its aggregation
ALS
In [amyotrophic lateral sclerosis](/diseases/als):
- Motor neuron degeneration releases HMGB1 into the spinal cord microenvironment
- [TDP-43](/proteins/tdp-43-protein) pathology promotes HMGB1 nuclear-to-cytoplasmic translocation
- Spinal cord microglia and [astrocytes](/entities/astrocytes) upregulate RAGE and TLR4 in ALS
- Serum HMGB1 levels correlate with disease progression rate and survival
Protein-Protein Interactions
| Partner | Interaction | Function |
|---|---|---|
| [Amyloid-β](/proteins/amyloid-beta-protein) | Direct binding | Inflammatory complex formation |
| [RAGE](/genes/rage) | Receptor-ligand | NF-κB activation |
| [TLR4](/genes/tlr4)/MD-2 | Receptor-ligand | Innate immune activation |
| [α-Synuclein](/proteins/alpha-synuclein) | Direct binding | Aggregation promotion |
| [p53](/genes/tp53) | Transcriptional cooperation | DNA damage response |
| CXCL12 | Heterocomplex | Chemotaxis enhancement |
| Nucleosomes | Chromatin interaction | Gene regulation |
| [Beclin-1](/proteins/beclin1-protein) | Direct binding | [Autophagy](/mechanisms/autophagy) regulation |
Pathway & Interaction Diagram
Interactive diagram showing HMGB1 key relationships in the SciDEX knowledge graph (15 connections shown).
Mermaid diagram (expand to render)
See Also
- [HMGB1 Gene](/genes/hmgb1) — Encoding gene
- [RAGE](/genes/rage) — Key receptor
- [TLR4](/genes/tlr4) — Pattern recognition receptor
- [Neuroinflammation](/mechanisms/neuroinflammation) — Central mechanism
- [NLRP3 Inflammasome](/mechanisms/nlrp3-inflammasome) — Downstream activation
External Links
- [HMGB1 at UniProt (P09429)](https://www.uniprot.org/uniprot/P09429)
- [HMGB1 at PDB (2YRQ)](https://www.rcsb.org/structure/2YRQ)
- [HMGB1 at Human Protein Atlas](https://www.proteinatlas.org/ENSG00000189403-HMGB1)
- [HMGB1 at AlphaFold](https://alphafold.ebi.ac.uk/entry/P09429)
Brain Atlas Resources
- [Allen Human Brain Atlas - Gene Expression](https://human.brain-map.org/microarray/search/show?search_term=HMGB1)
- [BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)
References
[Scaffidi et al., Release of chromatin protein HMGB1 by necrotic cells triggers inflammation (2002) (2002)](https://doi.org/10.1038/nature01023)
[Yang et al., MD-2 is required for disulfide HMGB1-dependent TLR4 signaling (2015) (2015)](https://doi.org/10.1084/jem.20141318)
[Venereau et al., Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release (2012) (2012)](https://doi.org/10.1084/jem.20120189)
[Fujita et al., HMGB1 induces neurite degeneration via TLR4-MARCKS in Alzheimer's disease (2016) (2016)](https://doi.org/10.1038/srep31895)
[Paudel et al., HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction (2018) (2018)](https://doi.org/10.3389/fnins.2018.00628)
[Unknown, Lotze & Tracey, High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal (2005) (2005)](https://doi.org/10.1038/nri1594)
[Unknown, Andersson & Tracey, HMGB1 is a therapeutic target for sterile inflammation and infection (2011) (2011)](https://doi.org/10.1146/annurev-immunol-030409-101323)