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Protein

High mobility group protein B1

Gene

HMGB1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability. Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury (PubMed:27362237). Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors. In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance (PubMed:23519706, PubMed:23446148, PubMed:23994764, PubMed:25048472). Has proangiogdenic activity (By similarity). May be involved in platelet activation (By similarity). Binds to phosphatidylserine and phosphatidylethanolamide (By similarity). Bound to RAGE mediates signaling for neuronal outgrowth (By similarity). May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP (PubMed:23303669, PubMed:25549101).By similarity4 Publications3 Publications
Nuclear functions are attributed to fully reduced HGMB1. Associates with chromatin and binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA, DNA-containing cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity (PubMed:20123072). May have an enhancing role in nucleotide excision repair (NER) (By similarity). However, effects in NER using in vitro systems have been reported conflictingly (PubMed:19446504, PubMed:19360789). May be involved in mismatch repair (MMR) and base excision repair (BER) pathways (PubMed:15014079, PubMed:16143102, PubMed:17803946). May be involved in double strand break repair such as non-homologous end joining (NHEJ) (By similarity). Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS) (By similarity). In vitro can displace histone H1 from highly bent DNA (By similarity). Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding (By similarity). Enhances binding of sterol regulatory element-binding proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and increases their transcriptional activities (By similarity). Facilitates binding of TP53 to DNA (PubMed:23063560). Proposed to be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1; however, this function has been questioned (By similarity). Can modulate the activity of the telomerase complex and may be involved in telomere maintenance (By similarity).By similarity2 Publications5 Publications
In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation (PubMed:20819940). Involved in oxidative stress-mediated autophagy (PubMed:21395369). Can protect BECN1 and ATG5 from calpain-mediated cleavage and thus proposed to control their proautophagic and proapoptotic functions and to regulate the extent and severity of inflammation-associated cellular injury (By similarity). In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy (By similarity). Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages (By similarity).By similarity2 Publications
In the extracellular compartment (following either active secretion or passive release) involved in regulation of the inflammatory response. Fully reduced HGMB1 (which subsequently gets oxidized after release) in association with CXCL12 mediates the recruitment of inflammatory cells during the initial phase of tissue injury; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization (PubMed:22370717). Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM (By similarity). Can bind to various types of DNA and RNA including microbial unmethylated CpG-DNA to enhance the innate immune response to nucleic acids. Proposed to act in promiscuous DNA/RNA sensing which cooperates with subsequent discriminative sensing by specific pattern recognition receptors (By similarity). Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE (PubMed:24971542). Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways. Mediates the release of cytokines/chemokines such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10 (PubMed:12765338, PubMed:18354232, PubMed:19264983, PubMed:20547845, PubMed:24474694). Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12 (PubMed:15607795). TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2 (PubMed:20547845). In bacterial LPS- or LTA-mediated inflammatory responses binds to the endotoxins and transfers them to CD14 for signaling to the respective TLR4:LY96 and TLR2 complexes (PubMed:18354232, PubMed:21660935, PubMed:25660311). Contributes to tumor proliferation by association with ACER/RAGE (By similarity). Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex (PubMed:18250463). Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1-containing chromatin immune complexes may also promote B cell responses to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent and ACER/RAGE-independent mechanism (By similarity). Inhibits phagocytosis of apoptotic cells by macrophages; the function is dependent on poly-ADP-ribosylation and involves binding to phosphatidylserine on the cell surface of apoptotic cells (By similarity). In adaptive immunity may be involved in enhancing immunity through activation of effector T cells and suppression of regulatory T (TReg) cells (PubMed:15944249, PubMed:22473704). In contrast, without implicating effector or regulatory T-cells, required for tumor infiltration and activation of T-cells expressing the lymphotoxin LTA:LTB heterotrimer thus promoting tumor malignant progression (By similarity). Also reported to limit proliferation of T-cells (By similarity). Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production (PubMed:19064698). Involved in induction of immunological tolerance by apoptotic cells; its pro-inflammatory activities when released by apoptotic cells are neutralized by reactive oxygen species (ROS)-dependent oxidation specifically on Cys-106 (PubMed:18631454). During macrophage activation by activated lymphocyte-derived self apoptotic DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes (By similarity).By similarity16 Publications

Miscellaneous

Proposed to contribute to the pathogenesis of various chronic inflammatory and autoimmune diseases, and cancer. High serum levels are found in several inflammatory events including sepsis, rheumatoid arthritis, artherosclerosis chronic kidney disease, systemic lupus erythematosus (SLE). Seems to be implicated in other diseases characterized by cell death and damage, including diabetes and Alzheimer's disease. Its nucleosome-associated release during secondory necrosis may play a role in SLE (PubMed:19064698). During chemotherapy can mediate regrowth and metastasis of remaining cells in a AGER/RAGE-depenedent manner (PubMed:23040637). Purified HMG box 1 acts as a specific antogonist to HGMB1 pro-inflammatory activities (PubMed:14695889).Curated2 Publications

Caution

Inconsistent experimental results may reflect the use of inconsistently defined redox forms. A recombinant fully reduced form has been used in a number of experiments. However, the redox states of HMGB1 administered in vivo, may interconvert among each other. Purified HMGB1 by itself has only weak pro-inflammatory activity.Curated

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi9 – 79HMG box 1PROSITE-ProRule annotationAdd BLAST71
DNA bindingi95 – 163HMG box 2PROSITE-ProRule annotationAdd BLAST69

GO - Molecular functioni

  • bubble DNA binding Source: AgBase
  • calcium-dependent protein kinase regulator activity Source: Ensembl
  • chemoattractant activity Source: UniProtKB
  • C-X-C chemokine binding Source: UniProtKB
  • cytokine activity Source: UniProtKB
  • damaged DNA binding Source: UniProtKB
  • DNA binding, bending Source: UniProtKB
  • DNA binding transcription factor activity Source: UniProtKB
  • DNA polymerase binding Source: UniProtKB
  • double-stranded DNA binding Source: UniProtKB
  • double-stranded RNA binding Source: Ensembl
  • four-way junction DNA binding Source: AgBase
  • integrin binding Source: BHF-UCL
  • lipopolysaccharide binding Source: UniProtKB
  • lyase activity Source: UniProtKB
  • phosphatidylserine binding Source: UniProtKB
  • protein kinase activator activity Source: Ensembl
  • RAGE receptor binding Source: UniProtKB
  • repressing transcription factor binding Source: UniProtKB
  • RNA binding Source: UniProtKB
  • single-stranded DNA binding Source: UniProtKB
  • single-stranded RNA binding Source: Ensembl
  • supercoiled DNA binding Source: AgBase
  • transcription factor binding Source: UniProtKB

GO - Biological processi

  • activation of innate immune response Source: UniProtKB
  • apoptotic cell clearance Source: UniProtKB
  • apoptotic DNA fragmentation Source: Reactome
  • autophagy Source: UniProtKB-KW
  • base-excision repair Source: Ensembl
  • chromatin assembly Source: Ensembl
  • dendritic cell chemotaxis Source: UniProtKB
  • DNA geometric change Source: AgBase
  • DNA ligation involved in DNA repair Source: UniProtKB
  • DNA recombination Source: UniProtKB
  • DNA topological change Source: UniProtKB
  • endothelial cell chemotaxis Source: Ensembl
  • endothelial cell proliferation Source: Ensembl
  • eye development Source: Ensembl
  • inflammatory response Source: CACAO
  • inflammatory response to antigenic stimulus Source: UniProtKB
  • innate immune response Source: Reactome
  • lung development Source: Ensembl
  • macrophage activation involved in immune response Source: Ensembl
  • myeloid dendritic cell activation Source: UniProtKB
  • negative regulation of apoptotic cell clearance Source: BHF-UCL
  • negative regulation of blood vessel endothelial cell migration Source: CACAO
  • negative regulation of CD4-positive, alpha-beta T cell differentiation Source: UniProtKB
  • negative regulation of interferon-gamma production Source: UniProtKB
  • negative regulation of RNA polymerase II transcriptional preinitiation complex assembly Source: UniProtKB
  • negative regulation of transcription by RNA polymerase II Source: UniProtKB
  • neuron projection development Source: UniProtKB
  • neutrophil clearance Source: UniProtKB
  • neutrophil degranulation Source: Reactome
  • plasmacytoid dendritic cell activation Source: Ensembl
  • positive regulation of activated T cell proliferation Source: UniProtKB
  • positive regulation of apoptotic process Source: UniProtKB
  • positive regulation of blood vessel endothelial cell migration Source: BHF-UCL
  • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • positive regulation of cytosolic calcium ion concentration Source: UniProtKB
  • positive regulation of dendritic cell differentiation Source: UniProtKB
  • positive regulation of DNA binding Source: UniProtKB
  • positive regulation of DNA ligation Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of glycogen catabolic process Source: Ensembl
  • positive regulation of interferon-alpha production Source: Ensembl
  • positive regulation of interferon-beta production Source: Ensembl
  • positive regulation of interleukin-10 production Source: UniProtKB
  • positive regulation of interleukin-12 production Source: UniProtKB
  • positive regulation of interleukin-1 beta secretion Source: Ensembl
  • positive regulation of interleukin-1 secretion Source: UniProtKB
  • positive regulation of interleukin-6 secretion Source: UniProtKB
  • positive regulation of JNK cascade Source: UniProtKB
  • positive regulation of MAPK cascade Source: UniProtKB
  • positive regulation of mismatch repair Source: UniProtKB
  • positive regulation of monocyte chemotactic protein-1 production Source: Ensembl
  • positive regulation of monocyte chemotaxis Source: UniProtKB
  • positive regulation of myeloid cell differentiation Source: Ensembl
  • positive regulation of NIK/NF-kappaB signaling Source: Ensembl
  • positive regulation of sprouting angiogenesis Source: Ensembl
  • positive regulation of toll-like receptor 2 signaling pathway Source: Ensembl
  • positive regulation of toll-like receptor 4 signaling pathway Source: Ensembl
  • positive regulation of toll-like receptor 9 signaling pathway Source: UniProtKB
  • positive regulation of transcription by RNA polymerase II Source: UniProtKB
  • positive regulation of tumor necrosis factor production Source: Ensembl
  • positive regulation of vascular endothelial cell proliferation Source: BHF-UCL
  • positive regulation of wound healing Source: Ensembl
  • regulation of autophagy Source: UniProtKB
  • regulation of nucleotide-excision repair Source: Ensembl
  • regulation of restriction endodeoxyribonuclease activity Source: UniProtKB
  • regulation of T cell mediated immune response to tumor cell Source: UniProtKB
  • regulation of tolerance induction Source: UniProtKB
  • regulation of transcription by RNA polymerase II Source: UniProtKB
  • response to glucocorticoid Source: Ensembl
  • T-helper 1 cell activation Source: UniProtKB
  • T-helper 1 cell differentiation Source: UniProtKB
  • toll-like receptor signaling pathway Source: Reactome
  • tumor necrosis factor secretion Source: UniProtKB
  • V(D)J recombination Source: UniProtKB

Keywordsi

Molecular functionDNA-binding
Biological processAdaptive immunity, Autophagy, Chemotaxis, DNA damage, DNA recombination, DNA repair, Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-HSA-1810476 RIP-mediated NFkB activation via ZBP1
R-HSA-211227 Activation of DNA fragmentation factor
R-HSA-3134963 DEx/H-box helicases activate type I IFN and inflammatory cytokines production
R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-HSA-5686938 Regulation of TLR by endogenous ligand
R-HSA-6798695 Neutrophil degranulation
R-HSA-879415 Advanced glycosylation endproduct receptor signaling
R-HSA-933542 TRAF6 mediated NF-kB activation
SIGNORiP09429

Names & Taxonomyi

Protein namesi
Recommended name:
High mobility group protein B1
Alternative name(s):
High mobility group protein 1
Short name:
HMG-1
Gene namesi
Name:HMGB1
Synonyms:HMG1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 13

Organism-specific databases

EuPathDBiHostDB:ENSG00000189403.14
HGNCiHGNC:4983 HMGB1
MIMi163905 gene
neXtProtiNX_P09429

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Chromosome, Cytoplasm, Endosome, Membrane, Nucleus, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi35S → A: Greatly reduces phosphorylation, nuclear localization; when associated with A-39; A-42; A-46; A-53 and A-181. 1 Publication1
Mutagenesisi35S → E: Cytoplasmic localization (phosphorylation mimicking); when associated with E-39; E-42; E-46; E-53 and E-181. 1 Publication1
Mutagenesisi39S → A: Greatly reduces phosphorylation, nuclear localization; when associated with A-35; A-42; A-46; A-53 and A-181. 1 Publication1
Mutagenesisi39S → E: Cytoplasmic localization (phosphorylation mimicking); when associated with E-35; E-42; E-46; E-53 and E-181. 1 Publication1
Mutagenesisi42S → A: Greatly reduces phosphorylation, nuclear localization; when associated with A-35; A-39; A-46; A-53 and A-181. 1 Publication1
Mutagenesisi42S → E: Cytoplasmic localization (phosphorylation mimicking); when associated with E-35; E-39; E-46; E-53 and E-181. 1 Publication1
Mutagenesisi46S → A: Greatly reduces phosphorylation, nuclear localization; when associated with A-35; A-39; A-42; A-53 and A-181. 1 Publication1
Mutagenesisi46S → E: Cytoplasmic localization (phosphorylation mimicking); when associated with E-35; E-39; E-42; E-53 and E-181. 1 Publication1
Mutagenesisi53S → A: Greatly reduces phosphorylation, nuclear localization; when associated with A-35; A-39; A-42; A-46 and A-181. 1 Publication1
Mutagenesisi53S → E: Cytoplasmic localization (phosphorylation mimicking); when associated with E-35; E-39; E-42; E-46 and E-181. 1 Publication1
Mutagenesisi67D → A: Abolishes cleavage by CASP1 and impairs ability to antagonize apoptosis-induced immune tolerance. 1 Publication1
Mutagenesisi106C → S: Inhibits oxidation-dependent inactivation of immunostimmulatory activity in apoptotic cells. 1 Publication1
Mutagenesisi181S → A: Greatly reduces phosphorylation, nuclear localization; when associated with A-35; A-39; A-42; A-46 and A-53. 1 Publication1
Mutagenesisi181S → E: Cytoplasmic localization (phosphorylation mimicking); when associated with E-35; E-39; E-42; E-46 and E-53. 1 Publication1

Organism-specific databases

DisGeNETi3146
OpenTargetsiENSG00000189403
PharmGKBiPA188

Chemistry databases

ChEMBLiCHEMBL2311236
DrugBankiDB05869 CTI-01

Polymorphism and mutation databases

BioMutaiHMGB1
DMDMi123369

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000485261 – 215High mobility group protein B1Add BLAST215

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei3N6-acetyllysineBy similarity1
Modified residuei7N6-acetyllysineBy similarity1
Modified residuei8N6-acetyllysineBy similarity1
Modified residuei12N6-acetyllysineBy similarity1
Disulfide bondi23 ↔ 45In disulfide HMGB1; alternateBy similarity
Modified residuei23Cysteine sulfonic acid (-SO3H); alternateBy similarity1
Modified residuei28N6-acetyllysineBy similarity1
Modified residuei29N6-acetyllysineBy similarity1
Modified residuei30N6-acetyllysineCombined sources1
Modified residuei35PhosphoserineCombined sources1
Modified residuei43N6-acetyllysineBy similarity1
Modified residuei45Cysteine sulfonic acid (-SO3H); alternateBy similarity1
Modified residuei90N6-acetyllysineBy similarity1
Modified residuei100PhosphoserineCombined sources1
Modified residuei106Cysteine sulfonic acid (-SO3H)By similarity1
Modified residuei127N6-acetyllysineBy similarity1
Modified residuei128N6-acetyllysineBy similarity1
Modified residuei141N6-acetyllysineBy similarity1
Modified residuei172N6-acetyllysineBy similarity1
Modified residuei173N6-acetyllysineBy similarity1
Modified residuei177N6-acetyllysineBy similarity1
Modified residuei180N6-acetyllysineBy similarity1
Modified residuei181ADP-ribosylserine1 Publication1
Modified residuei182N6-acetyllysineBy similarity1
Modified residuei183N6-acetyllysineBy similarity1
Modified residuei184N6-acetyllysineBy similarity1
Modified residuei185N6-acetyllysineBy similarity1

Post-translational modificationi

Phosphorylated at serine residues. Phosphorylation in both NLS regions is required for cytoplasmic translocation followed by secretion (PubMed:17114460).1 Publication
Acetylated on multiple sites upon stimulation with LPS (PubMed:22801494). Acetylation on lysine residues in the nuclear localization signals (NLS 1 and NLS 2) leads to cytoplasmic localization and subsequent secretion (By similarity). Acetylation on Lys-3 results in preferential binding to DNA ends and impairs DNA bending activity (By similarity).By similarity1 Publication
Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-106 and a possible intramolecular disulfide bond involving Cys-23 and Cys-45 give rise to different redox forms with specific functional activities in various cellular compartments: 1- fully reduced HMGB1 (HMGB1C23hC45hC106h), 2- disulfide HMGB1 (HMGB1C23-C45C106h) and 3- sulfonyl HMGB1 (HMGB1C23soC45soC106so).1 Publication3 Publications
Poly-ADP-ribosylated by PARP1 when secreted following stimulation with LPS (By similarity).By similarity
In vitro cleavage by CASP1 is liberating a HMG box 1-containing peptide which may mediate immunogenic activity; the peptide antagonizes apoptosis-induced immune tolerance (PubMed:24474694). Can be proteolytically cleaved by a thrombin:thrombomodulin complex; reduces binding to heparin and proinflammatory activities (By similarity).By similarity1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei10 – 11Cleavage; by thrombin:thrombomodulinBy similarity2
Sitei67 – 68Cleavage; by CASP11 Publication2

Keywords - PTMi

Acetylation, ADP-ribosylation, Disulfide bond, Oxidation, Phosphoprotein

Proteomic databases

EPDiP09429
MaxQBiP09429
PaxDbiP09429
PeptideAtlasiP09429
PRIDEiP09429
TopDownProteomicsiP09429

2D gel databases

DOSAC-COBS-2DPAGEiP09429

PTM databases

iPTMnetiP09429
PhosphoSitePlusiP09429
SwissPalmiP09429

Expressioni

Tissue specificityi

Ubiquituous. Expressed in platelets (PubMed:11154118).1 Publication

Gene expression databases

BgeeiENSG00000189403
CleanExiHS_HMGB1
ExpressionAtlasiP09429 baseline and differential
GenevisibleiP09429 HS

Organism-specific databases

HPAiCAB005873
HPA003506

Interactioni

Subunit structurei

Interacts (fully reduced HMGB1) with CXCL12; probably in a 1:2 ratio involving two molecules of CXCL12, each interacting with one HMG box of HMGB1; inhibited by glycyrrhizin (PubMed:22370717). Associates with the TLR4:LY96 receptor complex (PubMed:20547845). Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2 (By similarity). Interacts (in cytoplasm upon starvation) with BECN1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy (PubMed:20819940). Interacts with KPNA1; involved in nuclear import (PubMed:17114460). Interacts with SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT (By similarity). Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53 (PubMed:15014079, PubMed:18250463, PubMed:18160415, PubMed:19446504, PubMed:24474694, PubMed:23063560). Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response (PubMed:19264983). Interacts with THBD; prevents HGMB1 interaction with ACER/RAGE and inhibits HGMB1 proinflammatory activity (PubMed:15841214). Interacts with HAVCR2; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immume response (By similarity). Interacts with XPO1; mediating nuclear export (By similarity). Interacts with HTT (wild-type and mutant HTT with expanded polyglutamine repeat) (PubMed:23303669).By similarity14 Publications
(Microbial infection) Interacts with adenovirus protein pVII; this interaction immobilizes HMGB1 on chromatin, thus preventing its release from cell and subsequent inflammation activation.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • chemoattractant activity Source: UniProtKB
  • C-X-C chemokine binding Source: UniProtKB
  • cytokine activity Source: UniProtKB
  • DNA polymerase binding Source: UniProtKB
  • integrin binding Source: BHF-UCL
  • RAGE receptor binding Source: UniProtKB
  • repressing transcription factor binding Source: UniProtKB
  • transcription factor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi109389, 89 interactors
CORUMiP09429
DIPiDIP-24195N
IntActiP09429, 38 interactors
MINTiP09429
STRINGi9606.ENSP00000343040

Chemistry databases

BindingDBiP09429

Structurei

Secondary structure

1215
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi1 – 3Combined sources3
Beta strandi6 – 8Combined sources3
Helixi15 – 30Combined sources16
Helixi38 – 50Combined sources13
Helixi54 – 76Combined sources23
Beta strandi92 – 94Combined sources3
Helixi101 – 116Combined sources16
Beta strandi118 – 120Combined sources3
Helixi122 – 135Combined sources14
Helixi138 – 140Combined sources3
Helixi141 – 163Combined sources23

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2LY4NMR-A2-84[»]
2RTUNMR-A1-84[»]
2YRQNMR-A1-166[»]
ProteinModelPortaliP09429
SMRiP09429
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP09429

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 97Sufficient for interaction with HAVCR2By similarityAdd BLAST97
Regioni1 – 10Heparin-bindingBy similarity10
Regioni3 – 15LPS binding (delipidated)1 PublicationAdd BLAST13
Regioni80 – 96LPS binding (Lipid A)1 PublicationAdd BLAST17
Regioni89 – 108Cytokine-stimulating activity1 PublicationAdd BLAST20
Regioni150 – 183Binding to AGER/RAGEBy similarityAdd BLAST34

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi27 – 43Nuclear localization signal (NLS) 1By similarityAdd BLAST17
Motifi178 – 184Nuclear localization signal (NLS) 2By similarity7

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi186 – 215Asp/Glu-rich (acidic)Add BLAST30

Domaini

HMG box 2 mediates proinflammatory cytokine-stimulating activity and binding to TLR4 (PubMed:12765338, PubMed:20547845). However, not involved in mediating immunogenic activity in the context of apoptosis-induced immune tolerance (PubMed:24474694).3 Publications
The acidic C-terminal domain forms a flexible structure which can reversibly interact intramolecularily with the HMG boxes and modulate binding to DNA and other proteins (PubMed:23063560).By similarity1 Publication

Sequence similaritiesi

Belongs to the HMGB family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0381 Eukaryota
COG5648 LUCA
GeneTreeiENSGT00760000119164
HOGENOMiHOG000197861
HOVERGENiHBG009000
InParanoidiP09429
KOiK10802
OMAiYSQDKRP
OrthoDBiEOG091G0P81
PhylomeDBiP09429
TreeFamiTF105371

Family and domain databases

Gene3Di1.10.30.10, 2 hits
InterProiView protein in InterPro
IPR009071 HMG_box_dom
IPR036910 HMG_box_dom_sf
IPR017967 HMG_boxA_CS
PfamiView protein in Pfam
PF00505 HMG_box, 1 hit
PF09011 HMG_box_2, 1 hit
SMARTiView protein in SMART
SM00398 HMG, 2 hits
SUPFAMiSSF47095 SSF47095, 2 hits
PROSITEiView protein in PROSITE
PS00353 HMG_BOX_1, 1 hit
PS50118 HMG_BOX_2, 2 hits

Sequencei

Sequence statusi: Complete.

P09429-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKKCSERWK
60 70 80 90 100
TMSAKEKGKF EDMAKADKAR YEREMKTYIP PKGETKKKFK DPNAPKRPPS
110 120 130 140 150
AFFLFCSEYR PKIKGEHPGL SIGDVAKKLG EMWNNTAADD KQPYEKKAAK
160 170 180 190 200
LKEKYEKDIA AYRAKGKPDA AKKGVVKAEK SKKKKEEEED EEDEEDEEEE
210
EDEEDEDEEE DDDDE
Length:215
Mass (Da):24,894
Last modified:January 23, 2007 - v3
Checksum:i8A868CF277D417B5
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti143P → H in AAI41845 (PubMed:15489334).Curated1
Sequence conflicti215E → D in CAG33144 (Ref. 8) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04645111G → R in gastric-carcinoma cell line. 1 Publication1
Natural variantiVAR_046452149A → E in gastric-carcinoma cell line. 1 Publication1
Natural variantiVAR_046453156E → Q1 Publication1
Natural variantiVAR_046454190D → G in gastric-carcinoma cell line. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X12597 mRNA Translation: CAA31110.1
U51677 Genomic DNA Translation: AAB08987.1
D63874 mRNA Translation: BAA09924.1
EF157968 Genomic DNA Translation: ABM47301.1
AY377859 mRNA Translation: AAQ91389.1
AK291494 mRNA Translation: BAF84183.1
AK122825 mRNA Translation: BAG53745.1
CR749614 mRNA Translation: CAH18408.1
CR456863 mRNA Translation: CAG33144.1
BT006940 mRNA Translation: AAP35586.1
BT020159 mRNA Translation: AAV38961.1
EU012027 Genomic DNA Translation: ABS29271.1
AL353648 Genomic DNA No translation available.
CH471075 Genomic DNA Translation: EAX08457.1
BC003378 mRNA Translation: AAH03378.1
BC030981 mRNA Translation: AAH30981.1
BC066889 mRNA Translation: AAH66889.1
BC067732 mRNA Translation: AAH67732.1
BC141844 mRNA Translation: AAI41845.1
CCDSiCCDS9335.1
PIRiS02826
RefSeqiNP_001300821.1, NM_001313892.1
NP_001300822.1, NM_001313893.1
NP_002119.1, NM_002128.5
UniGeneiHs.434102
Hs.593339
Hs.596078

Genome annotation databases

EnsembliENST00000339872; ENSP00000343040; ENSG00000189403
ENST00000341423; ENSP00000345347; ENSG00000189403
ENST00000399494; ENSP00000382417; ENSG00000189403
ENST00000405805; ENSP00000384678; ENSG00000189403
GeneIDi3146
KEGGihsa:3146
UCSCiuc001usx.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiHMGB1_HUMAN
AccessioniPrimary (citable) accession number: P09429
Secondary accession number(s): A5D8W9
, Q14321, Q5T7C3, Q6IBE1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: January 23, 2007
Last modified: May 23, 2018
This is version 203 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 13
    Human chromosome 13: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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