IRAK1
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| Location (UCSC) | Chr X: 154.01 – 154.02 Mb | Chr X: 73.06 – 73.07 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene.[5][6] IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack.[7] IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.[8]
Structure
IRAK-1 contains an N-terminal death domain (
The proST domain contains serine, proline, and threonine amino acid residues and is used to facilitate IRAK-1 interaction with other IRAK family members or proteins. For example,
Moreover, IRAK-1 contains an invariant lysine within the centrally located kinase domain. The invariant lysine acts as a binding site for ATP and a mediator for catalytic function and kinase activity.[7][9]
IRAK-1 also contains a tyrosine residue (Tyr262) that conformationally changes the active site of the IRAK-1 by inhibiting the hydrophilic pocket behind the binding site and thereby allows the IRAK-1 to remain in an active state. For example, ATP binding to the IRAK-1 binding site can readily occur in the presence of Tyr266, because Tyr266 will occupy the hydrophilic pocket where ATP competitive inhibitors may bind and disrupt catalytic function.[7]
Activation
In the presence of foreign pathogens, IRAK-1 induced signaling pathways can be activated by Toll-like receptors (
IRAK-1 can also be activated upon interaction with other IRAK family members. IRAK-1 and IRAK-4 can activate each other by using the DD as a platform for MyD88. IRAK-4 first phosphorylates IRAK-1 which catalyzes an IRAK-1 auto-phosphorylation cascade, occurring in three steps. IRAK-1 is first phosphorylated at Thr209, causing a conformational change. Then, IRAK-1 is phosphorylated at Thr387 rendering IRAK-1 fully active. Finally, auto-phosphorylation at several residues in the proST region stimulates IRAK-1 release from the receptor complex.[7]
Function
The IRAK-1 encodes the interleukin-1 receptor-associated kinase 1, which is a serine-threonine protein
IRAK-1 kinase activity is not the sole protein involved in pro-inflammatory immune responses, however, it serves as an adaptor protein that effectively binds MyD88, IRAK-4, the toll-interacting proteins (TOLLIP)[15] together to form a complex that induces IL-1R-mediated NF-κB activation.[15][7]
Regulation
IRAK-1 activity is regulated during its activation and function. Auto-phosphorylation plays a role in IRAK-1 activation (see
Interactions
IRAK1 has been shown to
Clinical significance
IRAK-1 signaling is involved in rheumatoid arthritis.[35][36] Moreover, IRAK-1 plays a significant role in cancer.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000184216 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031392 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 9374458.
- S2CID 42977425.
- ^ PMID 25452754.
- ISBN 9780123838346.
- PMID 19689377.
- PMID 29208712.
- PMID 31156649.
- PMID 29038250.
- ^ "Entrez Gene: IRAK1 interleukin-1 receptor-associated kinase 1".
- PMID 16690127.
- ^ a b "TOLLIP toll interacting protein [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-03-05.
- ^ PMID 17890055.
- ^ PMID 18180283.
- ^ PMID 11096118.
- ^ PMID 18347055.
- PMID 11976320.
- ^ PMID 10383454.
- ^ PMID 11960013.
- S2CID 4333764.
- ^ a b c "IRAK1 Gene | IRAK1 Protein | IRAK1 Antibody". GeneCards Human Gene Database.
- PMID 11518704.
- S2CID 4269027.
- PMID 12566447.
- PMID 10920205.
- PMID 11259596.
- S2CID 28812149.
- PMID 18724939.
- PMID 18326498.
- S2CID 32036101.
- PMID 24772440.
- ^ "IRAK1 gene". Genetics Home Reference. U.S. National Library of Medicine. Archived from the original on 20 February 2017.
- PMID 30279971.
Further reading
- Auron PE (1999). "The interleukin 1 receptor: ligand interactions and signal transduction". Cytokine & Growth Factor Reviews. 9 (3–4): 221–237. PMID 9918122.
- Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature. 383 (6599): 443–446. S2CID 4269027.
- Brenner V, Nyakatura G, Rosenthal A, Platzer M (August 1997). "Genomic organization of two novel genes on human Xq28: compact head to head arrangement of IDH gamma and TRAP delta is conserved in rat and mouse". Genomics. 44 (1): 8–14. PMID 9286695.
- Huang J, Gao X, Li S, Cao Z (November 1997). "Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein". Proceedings of the National Academy of Sciences of the United States of America. 94 (24): 12829–12832. PMID 9371760.
- Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A (June 1998). "The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6)". The Journal of Experimental Medicine. 187 (12): 2097–2101. PMID 9625770.
- Maschera B, Ray K, Burns K, Volpe F (April 1999). "Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB". The Biochemical Journal. 339 (2): 227–231. PMID 10191251.
- Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". The Journal of Biological Chemistry. 274 (27): 19403–19410. PMID 10383454.
- Yang RB, Mark MR, Gurney AL, Godowski PJ (July 1999). "Signaling events induced by lipopolysaccharide-activated toll-like receptor 2". Journal of Immunology. 163 (2): 639–643. PMID 10395652.
- Thomas JA, Allen JL, Tsen M, Dubnicoff T, Danao J, Liao XC, et al. (July 1999). "Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase". Journal of Immunology. 163 (2): 978–984. PMID 10395695.
- Reichwald K, Thiesen J, Wiehe T, Weitzel J, Poustka WA, Rosenthal A, et al. (March 2000). "Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions". Mammalian Genome. 11 (3): 182–190. S2CID 15901911.
- Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al. (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nature Cell Biology. 2 (6): 346–351. S2CID 32036101.
- Böl G, Kreuzer OJ, Brigelius-Flohé R (July 2000). "Translocation of the interleukin-1 receptor-associated kinase-1 (IRAK-1) into the nucleus". FEBS Letters. 477 (1–2): 73–78. PMID 10899313.
- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–1795. PMID 11076863.
- Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, et al. (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". The Journal of Biological Chemistry. 276 (11): 7859–7866. PMID 11096118.
- Li X, Commane M, Jiang Z, Stark GR (April 2001). "IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK)". Proceedings of the National Academy of Sciences of the United States of America. 98 (8): 4461–4465. PMID 11287640.
- Jensen LE, Whitehead AS (August 2001). "IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability". The Journal of Biological Chemistry. 276 (31): 29037–29044. PMID 11397809.
- Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (November 2001). "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B". The Journal of Biological Chemistry. 276 (45): 41661–41667. PMID 11518704.
