High mobility group protein B1

Details

Name
High mobility group protein B1
Synonyms
  • High mobility group protein 1
  • HMG-1
  • HMG1
Gene Name
HMGB1
Organism
Humans
Amino acid sequence
>lcl|BSEQ0021855|High mobility group protein B1
MGKGDPKKPRGKMSSYAFFVQTCREEHKKKHPDASVNFSEFSKKCSERWKTMSAKEKGKF
EDMAKADKARYEREMKTYIPPKGETKKKFKDPNAPKRPPSAFFLFCSEYRPKIKGEHPGL
SIGDVAKKLGEMWNNTAADDKQPYEKKAAKLKEKYEKDIAAYRAKGKPDAAKKGVVKAEK
SKKKKEEEEDEEDEEDEEEEEDEEDEDEEEDDDDE
Number of residues
215
Molecular Weight
24893.58
Theoretical pI
5.42
GO Classification
Functions
bubble DNA binding / C-X-C chemokine binding / chemoattractant activity / chromatin binding / cytokine activity / damaged DNA binding / DNA binding, bending / DNA polymerase binding / double-stranded DNA binding / double-stranded RNA binding / four-way junction DNA binding / lipopolysaccharide binding / lyase activity / poly(A) RNA binding / RAGE receptor binding / repressing transcription factor binding / single-stranded DNA binding / single-stranded RNA binding / supercoiled DNA binding / transcription factor activity, sequence-specific DNA binding / transcription factor binding
Processes
activation of innate immune response / adaptive immune response / apoptotic DNA fragmentation / apoptotic process / autophagy / cellular component disassembly involved in execution phase of apoptosis / chromatin remodeling / dendritic cell chemotaxis / DNA geometric change / DNA ligation involved in DNA repair / DNA recombination / DNA topological change / endothelial cell chemotaxis / endothelial cell proliferation / inflammatory response / inflammatory response to antigenic stimulus / innate immune response / macrophage activation involved in immune response / myeloid dendritic cell activation / negative regulation of apoptotic cell clearance / negative regulation of blood vessel endothelial cell migration / negative regulation of RNA polymerase II transcriptional preinitiation complex assembly / negative regulation of transcription from RNA polymerase II promoter / neuron projection development / plasmacytoid dendritic cell activation / positive chemotaxis / positive regulation of apoptotic process / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of cytosolic calcium ion concentration / positive regulation of DNA binding / positive regulation of ERK1 and ERK2 cascade / positive regulation of interferon-alpha production / positive regulation of interferon-beta production / positive regulation of interleukin-1 beta secretion / positive regulation of interleukin-1 secretion / positive regulation of interleukin-6 secretion / positive regulation of JNK cascade / positive regulation of MAPK cascade / positive regulation of mismatch repair / positive regulation of monocyte chemotaxis / positive regulation of sprouting angiogenesis / positive regulation of transcription from RNA polymerase II promoter / positive regulation of tumor necrosis factor production / positive regulation of wound healing / programmed cell death / regulation of autophagy / regulation of restriction endodeoxyribonuclease activity / regulation of tolerance induction / regulation of transcription from RNA polymerase II promoter / tumor necrosis factor secretion / V(D)J recombination
Components
cell surface / condensed chromosome / cytosol / early endosome / endoplasmic reticulum-Golgi intermediate compartment / extracellular region / extracellular space / nucleoplasm / nucleus / plasma membrane
General Function
Transcription factor binding
Specific Function
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 (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).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).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).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).
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0021856|High mobility group protein B1 (HMGB1)
ATGGGCAAAGGAGATCCTAAGAAGCCGAGAGGCAAAATGTCATCATATGCATTTTTTGTG
CAAACTTGTCGGGAGGAGCATAAGAAGAAGCACCCAGATGCTTCAGTCAACTTCTCAGAG
TTTTCTAAGAAGTGCTCAGAGAGGTGGAAGACCATGTCTGCTAAAGAGAAAGGAAAATTT
GAAGATATGGCAAAAGCGGACAAGGCCCGTTATGAAAGAGAAATGAAAACCTATATCCCT
CCCAAAGGGGAGACAAAAAAGAAGTTCAAGGATCCCAATGCACCCAAGAGGCCTCCTTCG
GCCTTCTTCCTCTTCTGCTCTGAGTATCGCCCAAAAATCAAAGGAGAACATCCTGGCCTG
TCCATTGGTGATGTTGCGAAGAAACTGGGAGAGATGTGGAATAACACTGCTGCAGATGAC
AAGCAGCCTTATGAAAAGAAGGCTGCGAAGCTGAAGGAAAAATACGAAAAGGATATTGCT
GCATATCGAGCTAAAGGAAAGCCTGATGCAGCAAAAAAGGGAGTTGTCAAGGCTGAAAAA
AGCAAGAAAAAGAAGGAAGAGGAGGAAGATGAGGAAGATGAAGAGGATGAGGAGGAGGAG
GAAGATGAAGAAGATGAAGATGAAGAAGAAGATGATGATGATGAATAA
Chromosome Location
13
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP09429
UniProtKB Entry NameHMGB1_HUMAN
GenBank Gene IDX12597
GenAtlas IDHMGB1
HGNC IDHGNC:4983
General References
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Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB05869Ethyl pyruvateinvestigationalunknownDetails
DB00608Chloroquineapproved, investigational, vet_approvedunknowninhibitorDetails