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Protein

High mobility group protein B1

Gene

HMGB1

Organism
Equus caballus (Horse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript 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. 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. Has proangiogenic activity. May be involved in platelet activation. Binds to phosphatidylserine and phosphatidylethanolamide. Bound to RAGE mediates signaling for neuronal outgrowth. May play a role in accumulation of expanded polyglutamine (polyQ) proteins.By similarity
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. May be involved in nucleotide excision repair (NER), mismatch repair (MMR) and base excision repair (BER) pathways, and double strand break repair such as non-homologous end joining (NHEJ). 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). In vitro can displace histone H1 from highly bent DNA. Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding. Enhances binding of sterol regulatory element-binding proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and increases their transcriptional activities. Facilitates binding of TP53 to DNA. May be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1. Can modulate the activity of the telomerase complex and may be involved in telomere maintenance.By similarity
In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation. 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. In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy. Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages.By similarity
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. Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM. 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. Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE. 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. Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12. TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2. 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. Contributes to tumor proliferation by association with ACER/RAGE. Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex. 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. 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. In adaptive immunity may be involved in enhancing immunity through activation of effector T-cells and suppression of regulatory T (TReg) cells. 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. Also reported to limit proliferation of T-cells. Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production. 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. During macrophage activation by activated lymphocyte-derived self apoptotic DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes.By similarity

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi9 – 79HMG box 1Add BLAST71
DNA bindingi95 – 163HMG box 2Add BLAST69

GO - Molecular functioni

GO - Biological processi

Keywordsi

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

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
OrganismiEquus caballus (Horse)
Taxonomic identifieri9796 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaPerissodactylaEquidaeEquus
Proteomesi
  • UP000002281 Componenti: Chromosome 17

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002691781 – 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-acetyllysineBy similarity1
Modified residuei35PhosphoserineBy similarity1
Modified residuei43N6-acetyllysineBy similarity1
Modified residuei45Cysteine sulfonic acid (-SO3H); alternateBy similarity1
Modified residuei90N6-acetyllysineBy similarity1
Modified residuei100PhosphoserineBy similarity1
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-ribosylserineBy similarity1
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.By similarity
Acetylated on multiple sites upon stimulation with LPS (By similarity). Acetylation on lysine residues in the nuclear localization signals (NLS 1 and NLS 2) leads to cytoplasmic localization and subsequent secretion. Acetylation on Lys-3 results in preferential binding to DNA ends and impairs DNA bending activity (By similarity).By similarity
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).By similarity
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. Can be proteolytically cleaved by a thrombin:thrombomodulin complex; reduces binding to heparin and proinflammatory activities (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei10 – 11Cleavage; by thrombin:thrombomodulinBy similarity2
Sitei67 – 68Cleavage; by CASP1By similarity2

Keywords - PTMi

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

Proteomic databases

PaxDbiQ08IE6.

Expressioni

Gene expression databases

BgeeiENSECAG00000008439.
ExpressionAtlasiQ08IE6. baseline.

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. Associates with the TLR4:LY96 receptor complex. Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2. Interacts (in cytoplasm upon starvation) with BECN1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy. Interacts with KPNA1; involved in nuclear import. Interacts with SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT. Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53. Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response. Interacts with THBD; prevents HGMB1 interaction with ACER/RAGE and inhibits HGMB1 proinflammatory activity. Interacts with HAVCR2; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immume response. Interacts with XPO1; mediating nuclear export.By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi9796.ENSECAP00000006518.

Structurei

3D structure databases

ProteinModelPortaliQ08IE6.
SMRiQ08IE6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 97Sufficient for interaction with HAVCR2By similarityAdd BLAST97
Regioni1 – 10Heparin-bindingBy similarity10
Regioni3 – 15LPS binding (delipidated)By similarityAdd BLAST13
Regioni27 – 43NLS 1By similarityAdd BLAST17
Regioni80 – 96LPS binding (Lipid A)By similarityAdd BLAST17
Regioni89 – 108Cytokine-stimulating activityBy similarityAdd BLAST20
Regioni150 – 183Binding to AGER/RAGEBy similarityAdd BLAST34
Regioni178 – 184NLS 2By similarity7

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 biasi28 – 185Lys-richAdd BLAST158
Compositional biasi186 – 215Glu-richAdd BLAST30

Domaini

HMG box 2 mediates proinflammatory cytokine-stimulating activity and binding to TLR4. However, not involved in mediating immunogenic activity in the context of apoptosis-induced immune tolerance.By similarity
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.By similarity

Sequence similaritiesi

Belongs to the HMGB family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0381. Eukaryota.
COG5648. LUCA.
GeneTreeiENSGT00760000119164.
HOGENOMiHOG000197861.
HOVERGENiHBG009000.
InParanoidiQ08IE6.
KOiK10802.
OMAiYSQDKRP.
OrthoDBiEOG091G0P81.
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.

Q08IE6-1 [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

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB275457 mRNA. Translation: BAF33339.1.
RefSeqiNP_001075304.1. NM_001081835.2.
UniGeneiEca.13960.
Eca.18721.
Eca.67.

Genome annotation databases

EnsembliENSECAT00000008670; ENSECAP00000006518; ENSECAG00000008439.
GeneIDi100033873.
KEGGiecb:100033873.

Similar proteinsi

Entry informationi

Entry nameiHMGB1_HORSE
AccessioniPrimary (citable) accession number: Q08IE6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 12, 2006
Last sequence update: January 23, 2007
Last modified: October 25, 2017
This is version 88 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families