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Protein

High mobility group protein B1

Gene

HMGB1

Organism
Canis lupus familiaris (Dog) (Canis familiaris)
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)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi9 – 7971HMG box 1PROSITE-ProRule annotationAdd
BLAST
DNA bindingi95 – 16369HMG box 2PROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Adaptive immunity, Autophagy, Chemotaxis, DNA damage, DNA recombination, DNA repair, Immunity, Inflammatory response, Innate immunity

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiR-CFA-1810476. RIP-mediated NFkB activation via ZBP1.
R-CFA-211227. Activation of DNA fragmentation factor.
R-CFA-3134963. DEx/H-box helicases activate type I IFN and inflammatory cytokines production.
R-CFA-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-CFA-879415. Advanced glycosylation endproduct receptor signaling.
R-CFA-933542. TRAF6 mediated NF-kB activation.

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
OrganismiCanis lupus familiaris (Dog) (Canis familiaris)
Taxonomic identifieri9615 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCarnivoraCaniformiaCanidaeCanis
Proteomesi
  • UP000002254 Componenti: Chromosome 25

Subcellular locationi

  • Nucleus By similarity
  • Chromosome By similarity
  • Cytoplasm By similarity
  • Secreted By similarity
  • Cell membrane By similarity; Peripheral membrane protein By similarity; Extracellular side By similarity
  • Endosome By similarity
  • Endoplasmic reticulum-Golgi intermediate compartment By similarity

  • Note: In basal state predominantly nuclear. Shuttles between the cytoplasm and the nucleus. Translocates from the nucleus to the cytoplasm upon autophagy stimulation. Release from macrophages in the extracellular milieu requires the activation of NLRC4 or NLRP3 inflammasomes (By similarity). Passively released to the extracellular milieu from necrotic cells by diffusion, involving the fully reduced HGMB1 which subsequently gets oxidized. Also released from apoptic cells. Active secretion from a variety of immune and non-immune cells such as macrophages, monocytes, neutrophils, dendritic cells, natural killer cells and plasma cells in response to various stimuli such as LPS and cytokines involves a nonconventional secretory process via secretory lysosomes. Found on the surface of activated platelets.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 215214High mobility group protein B1PRO_0000048524Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei3 – 31N6-acetyllysineBy similarity
Modified residuei7 – 71N6-acetyllysineBy similarity
Modified residuei8 – 81N6-acetyllysineBy similarity
Modified residuei12 – 121N6-acetyllysineBy similarity
Disulfide bondi23 ↔ 45In disulfide HMGB1By similarity
Modified residuei23 – 231Cysteine derivative; cysteine sulfonic acid (-SO(3)H) in sulfonyl HMGB1; alternateBy similarity
Modified residuei28 – 281N6-acetyllysineBy similarity
Modified residuei29 – 291N6-acetyllysineBy similarity
Modified residuei30 – 301N6-acetyllysineBy similarity
Modified residuei35 – 351PhosphoserineBy similarity
Modified residuei43 – 431N6-acetyllysineBy similarity
Modified residuei45 – 451Cysteine derivative; cysteine sulfonic acid (-SO(3)H) in sulfonyl HMGB1; alternateBy similarity
Modified residuei90 – 901N6-acetyllysineBy similarity
Modified residuei100 – 1001PhosphoserineBy similarity
Modified residuei106 – 1061Cysteine derivative; cysteine sulfonic acid (-SO(3)H) in sulfonyl HMGB1By similarity
Cross-linki112 – 112Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei127 – 1271N6-acetyllysineBy similarity
Modified residuei128 – 1281N6-acetyllysineBy similarity
Modified residuei141 – 1411N6-acetyllysineBy similarity
Modified residuei172 – 1721N6-acetyllysineBy similarity
Modified residuei173 – 1731N6-acetyllysineBy similarity
Modified residuei177 – 1771N6-acetyllysineBy similarity
Modified residuei180 – 1801N6-acetyllysineBy similarity
Modified residuei182 – 1821N6-acetyllysineBy similarity
Modified residuei183 – 1831N6-acetyllysineBy similarity
Modified residuei184 – 1841N6-acetyllysineBy similarity
Modified residuei185 – 1851N6-acetyllysineBy similarity

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)LengthDescriptionGraphical viewFeature identifierActions
Sitei10 – 112Cleavage; by thrombin:thrombomodulinBy similarity
Sitei67 – 682Cleavage; by CASP1By similarity

Keywords - PTMi

Acetylation, Disulfide bond, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ6YKA4.
PRIDEiQ6YKA4.

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

Protein-protein interaction databases

STRINGi9615.ENSCAFP00000009862.

Chemistry

BindingDBiQ6YKA4.

Structurei

3D structure databases

ProteinModelPortaliQ6YKA4.
SMRiQ6YKA4. Positions 5-166.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni2 – 9796Sufficient for interaction with HAVCR2By similarityAdd
BLAST
Regioni2 – 109Heparin-bindingBy similarity
Regioni3 – 1513LPS binding (delipidated)By similarityAdd
BLAST
Regioni27 – 4317NLS 1By similarityAdd
BLAST
Regioni80 – 9617LPS binding (Lipid A)By similarityAdd
BLAST
Regioni89 – 10820Cytokine-stimulating activityBy similarityAdd
BLAST
Regioni150 – 18334Binding to AGER/RAGEBy similarityAdd
BLAST
Regioni178 – 1847NLS 2By similarity

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi27 – 4317Nuclear localization signal (NLS) 1By similarityAdd
BLAST
Motifi178 – 1847Nuclear localization signal (NLS) 2By similarity

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi186 – 21530Asp/Glu-rich (acidic)Add
BLAST

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
Contains 2 HMG box DNA-binding domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0381. Eukaryota.
COG5648. LUCA.
GeneTreeiENSGT00760000119164.
HOGENOMiHOG000197861.
HOVERGENiHBG009000.
InParanoidiQ6YKA4.
KOiK10802.
OMAiRMSAYAF.
TreeFamiTF105371.

Family and domain databases

Gene3Di1.10.30.10. 2 hits.
InterProiIPR009071. HMG_box_dom.
IPR017967. HMG_boxA_CS.
[Graphical view]
PfamiPF00505. HMG_box. 1 hit.
PF09011. HMG_box_2. 1 hit.
[Graphical view]
SMARTiSM00398. HMG. 2 hits.
[Graphical view]
SUPFAMiSSF47095. SSF47095. 2 hits.
PROSITEiPS00353. HMG_BOX_1. 1 hit.
PS50118. HMG_BOX_2. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q6YKA4-1 [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
AY135519 mRNA. Translation: AAN11296.1.
AY135521 Genomic DNA. Translation: AAN11319.1.
RefSeqiNP_001002937.1. NM_001002937.2.
XP_013962798.1. XM_014107323.1.
UniGeneiCfa.416.
Cfa.46947.

Genome annotation databases

EnsembliENSCAFT00000010639; ENSCAFP00000009862; ENSCAFG00000006597.
GeneIDi403170.
KEGGicfa:403170.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY135519 mRNA. Translation: AAN11296.1.
AY135521 Genomic DNA. Translation: AAN11319.1.
RefSeqiNP_001002937.1. NM_001002937.2.
XP_013962798.1. XM_014107323.1.
UniGeneiCfa.416.
Cfa.46947.

3D structure databases

ProteinModelPortaliQ6YKA4.
SMRiQ6YKA4. Positions 5-166.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9615.ENSCAFP00000009862.

Chemistry

BindingDBiQ6YKA4.

Proteomic databases

PaxDbiQ6YKA4.
PRIDEiQ6YKA4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSCAFT00000010639; ENSCAFP00000009862; ENSCAFG00000006597.
GeneIDi403170.
KEGGicfa:403170.

Organism-specific databases

CTDi3146.

Phylogenomic databases

eggNOGiKOG0381. Eukaryota.
COG5648. LUCA.
GeneTreeiENSGT00760000119164.
HOGENOMiHOG000197861.
HOVERGENiHBG009000.
InParanoidiQ6YKA4.
KOiK10802.
OMAiRMSAYAF.
TreeFamiTF105371.

Enzyme and pathway databases

ReactomeiR-CFA-1810476. RIP-mediated NFkB activation via ZBP1.
R-CFA-211227. Activation of DNA fragmentation factor.
R-CFA-3134963. DEx/H-box helicases activate type I IFN and inflammatory cytokines production.
R-CFA-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-CFA-879415. Advanced glycosylation endproduct receptor signaling.
R-CFA-933542. TRAF6 mediated NF-kB activation.

Miscellaneous databases

NextBioi20816914.

Family and domain databases

Gene3Di1.10.30.10. 2 hits.
InterProiIPR009071. HMG_box_dom.
IPR017967. HMG_boxA_CS.
[Graphical view]
PfamiPF00505. HMG_box. 1 hit.
PF09011. HMG_box_2. 1 hit.
[Graphical view]
SMARTiSM00398. HMG. 2 hits.
[Graphical view]
SUPFAMiSSF47095. SSF47095. 2 hits.
PROSITEiPS00353. HMG_BOX_1. 1 hit.
PS50118. HMG_BOX_2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].

Entry informationi

Entry nameiHMGB1_CANLF
AccessioniPrimary (citable) accession number: Q6YKA4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 15, 2005
Last sequence update: January 23, 2007
Last modified: May 11, 2016
This is version 97 of the entry and version 3 of the sequence. [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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.