High Mobility Group Protein B1

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High Mobility Group Protein B1

Existing structural data : 2yrq

Properties of human protein
Mass / length primary structure 214 amino acids
Identifier
Gene name HMGB1
External IDs
Occurrence
Homology family HMGB
Parent taxon Eukaryotes

HMGB1 (HMGB1) , one is high-mobility group - protein that is released from dead cells ( necrosis ) and physiologically than the body's own alarm substance is used. High concentrations in the blood often indicate serious or even fatal disease, for example, blood poisoning ( sepsis ), or the final stage of malaria . HMGB1 also plays an important role in tumor development and immune defense . In animal models and in clinical studies it could be shown that HMGB1 is also involved in the development of numerous rheumatic diseases. In healthy cells, HMGB1 is also involved in gene expression , the reading of the genetic make-up ( transcription ).

Due to its complex functions, HMGB1 is currently being intensively researched. The inhibition (inhibition) of HMGB1 promises new possibilities for the therapy of numerous serious diseases.

Synonyms

HMGB1, HMG1, amphoterine

structure

HMGB1 is a member of the high-mobility group box proteins class of DNA-binding proteins . It is human-coded for 13q12, has 215 amino acids, has a mathematical weight of 24,762 Daltons and migrates electrophoretically at 30 kDa. Structural motifs are two positively charged DNA-binding elements, the A-box (1-79) and the B-box (89-163) as well as an acidic component c-terminal 166-215 with a high proportion of asparagine and glutamate. The protein has two nuclear localization sequences NLS1 at 28-44 and NLS2 at 180-185. It binds the DNA unspecifically in the minor grove and bends it (bends) so that other DNA-binding proteins, for example transcription factors, can bind to it. It is post-translationally modified in various forms: acetylation at lysine, methylation , ADP-ribosylation , phosphorylation , glycosylation . The extent of acetylation at nuclear localization sequences determines, for example, whether the protein migrates into the nucleus or is actively secreted.

Receptors and signal transduction

Well-known receptors are RAGE , TLR-4 and TLR-2 , the most important activated elements of signal transduction are p38-MAPK and NF-κB .

Biological effects

Activated cells then form various cytokines, adhesion molecules, iNOS (peroxynitrite), for example. Neutrophilic granulocytes, monocytes, macrophages and dendritz cells are activated, vascular endothelia express adhesion receptors and become permeable (consequence: vascular leak with tissue edema, reduced tissue perfusion), as well as intestinal epithelia (consequence: transfer of intestinal bacteria into the bloodstream). For example, mesoangioblasts and other stem cells are activated in the sense of a later tissue repair.

Diseases

Autoimmune diseases for which a meaning is discussed are systemic lupus erythematosus , rheumatoid arthritis , treatment-resistant epilepsy and, if one wishes to understand microinflammation as such, atherosclerosis .

Diseases of secondary organism damage are sepsis and other forms of systemic inflammation , processes of necrosis with unregulated cell death such as ischemia-reperfusion in organ transplantation , stroke , embolism .

Concept sepsis

Sepsis see there; In the early phase of contact with germs, various of their structural elements are quickly identified and the immune system is activated in an unspecific manner, with tumor necrosis factor and interleukin 1 being formed as the earliest mediators . HMGB1 was sought in the conception and discovered in this function as 'a cytokine formed late by activated macrophages'. It is the first in the chronological order of the formed mediators, which was shown to be clinically transformable in animal experiments of different sepsis models as therapeutically successfully inhibited.

Inhibitors

Are known minocycline , ethyl pyruvate , acetylcholine , nicotine as agonists at α 7 -nikotinischen acetylcholine receptor , as well as Steaoryl- lysophosphatidylcholine .

Individual evidence

  1. ↑ a b D. S. Pisetsky, H. Erlandsson-Harris, U. Andersson: High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease. In: Arthritis Res Ther . 10, 2008, p. 209. PMID 18598385
  2. ↑ LM Alleva, AC Budd, IA Clark: Systemic release of high mobility group box 1 protein during severe murine influenza. In: J Immunol. 181, 2008, pp. 1454-1459. PMID 18606700
  3. ↑ L. Campana, L. Bosurgi, P. Rovere-Querini: HMGB1: a two-headed signal regulating tumor progression and immunity. In: Curr Opin Immunol . 20, 2008, pp. 518-523. PMID 18599281
  4. ↑ Lauren Elizabeth Walker, Federica Frigerio, Teresa Ravizza, Emanuele Ricci, Karen Tse: Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy . In: The Journal of Clinical Investigation . tape 127 , no. 6 , June 1, 2017, ISSN  1558-8238 , p. 2118–2132 , doi : 10.1172 / JCI92001 , PMID 28504645 , PMC 5451237 (free full text).

literature

  • L. Ulona et al: High-mobility group box 1 (HMGB1) protein - Friedn and foe. In: Cytokine and Growth Factor Reviews. Amsterdam 17, 2006, pp. 189-201. ISSN  1359-6101
  • K. Hayakawa et al .: Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1 inhibiting mechanism. In: Stroke. 39, 3, 2008, pp. 951-958. (on-line)