HMGB1 Protein

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HMGB1 Protein

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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.

...

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)

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)

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Related Entities

HMGB1PROTEIN

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slug	proteins-hmgb1-protein
kg_node_id	HMGB1PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d00530945f56
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-hmgb1-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

17

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HMGB1 Protein

HMGB1 Protein

HMGB1 Protein

HMGB1 Protein

Overview

Structure

Domain Organization

Critical Cysteine Residues

Crystal Structure

Function and Signaling

Intranuclear Functions

DAMP Signaling Cascade

Secretion Mechanisms

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

ALS

Protein-Protein Interactions

Pathway & Interaction Diagram

See Also

External Links

Brain Atlas Resources

References

💬 Discussion