Interleukin-17 receptor

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Interleukin-17 receptor
Identifiers
SymbolIL17R
PfamPF08357
InterProIPR013568
Membranome8
interleukin 17 receptor A
File:5JVF.pdb.jpg
Crystal structure of a complex of IL-17RA bound to IL-17F in a 1:2 stoichiometry.[1]
Identifiers
SymbolIL17RA
Alt. symbolsIL17R, CDw217
Entrez23765
HUGO5985
OMIM605461
RefSeqNM_014339
UniProtQ96F46
Other data
LocusChr. 22 q11.1
interleukin 17 receptor B
Identifiers
SymbolIL17RB
Alt. symbolsIL17BR
Entrez55540
HUGO18015
OMIM605458
RefSeqNM_172234
UniProtQ9NRM6
Other data
LocusChr. 3 p21.1
interleukin 17 receptor C
Identifiers
SymbolIL17RC
Alt. symbolsIL17-RL
Entrez84818
HUGO18358
OMIM610925
RefSeqNM_032732
UniProtQ8NAC3
Other data
LocusChr. 3 p25.3
Interleukin 17 receptor D
Identifiers
SymbolIL17RD
Alt. symbolsSEF, IL17RLM, FLJ35755, IL-17RD
Entrez54756
HUGO17616
OMIM606807
RefSeqNM_017563
UniProtQ8NFM7
Other data
LocusChr. 3 p21.1
interleukin 17 receptor E
Identifiers
SymbolIL17RE
Alt. symbolsFLJ23658
Entrez132014
HUGO18439
RefSeqNM_153480
UniProtQ8NFR9
Other data
LocusChr. 3 p25.3
Interleukin 17 receptor E-like
Identifiers
SymbolIL17REL
Entrez400935
HUGO33808
RefSeqNM_001001694
UniProtQ6ZVW7
Other data
LocusChr. 22 q13.33

Interleukin-17 receptor (IL-17R) is a cytokine receptor which binds interleukin 17A.[2] Functional IL-17R is a heteromeric complex consisting of at least IL17RA and IL17RC.[3]

A number of additional variants exist including IL17RB,[4] which binds preferentially IL17B and IL17E.[5][6] A total of five members of the family have been identified.[7] The first identified member, IL-17RA is located on human chromosome 22.

Evolution

There are two IL17Rs (IL17RA and IL17RD) in the genome of the basal chordate Amphioxus.[8] After two rounds of whole genome duplications, these two IL17R genes expanded into five early vertebrate IL17R genes, IL17RA to IL17RE. Two (IL17RA and IL17RD) are found in most vertebrates, whereas the other three (IL17RB, ILR17RC and IL17RE) have undergone some losses in vertebrates during evolution.

Structure

IL-17RA is the founding member of a new IL-17R(A-E) subfamily of cytokine receptors. IL-17RA is by far the largest member of the family and has the largest cytoplasmic tail of the family. This cytoplasmic tail provides docking sites for numerous signaling intermediates. IL-17RA is composed of both alpha helices and beta sheets and has fibronectin domains, beta-sandwich domains, and ectodomains.[9]

Distribution

IL-17 RA has been observed at high levels in certain tissues such as: haematopoietic, bone marrow, thymus, and spleen tissue. IL-17 RA is also normally found in low levels in colon, small intestine, and lung tissues.[10]

Expression and regulation

IL-17RA is expressed in CD8+ T cells, and upregulated by IL-15 and IL-21.[10] IL-17RA may be internalised after binding IL-17A.[10]

IL-17RC expression is low in haematopoietic tissues and high in non-immune cells of the prostate, liver, kidney, thyroid and joints.[10]

Clinical significance

As of 2010 IL-17A neutralizing antibodies have the potential for the treatment of autoimmune diseases in humans. It also may soon be used for protection against periodontal bone loss as it is currently being tested in mice. IL-17 RA has been observed at high levels in people undergoing treatment for cardiac fibroblasts and in certain tissues such as: haematopoietic, bone marrow, thymus, and spleen tissue.[10]

As therapy targets

Approved anti-IL17(R) drugs include : Brodalumab (Siliq), an antibody to the receptor, approved for psoriasis. Ixekizumab, approved for plaque psoriasis, is an antibody to IL-17 itself (rather than the receptor).

See also

References

  1. PDB: 3JVF​; Ely LK, Fischer S, Garcia KC (December 2009). "Structural basis of receptor sharing by interleukin 17 cytokines". Nat. Immunol. 10 (12): 1245–51. doi:10.1038/ni.1813. PMC 2783927. PMID 19838198.
  2. Yao Z, Spriggs MK, Derry JM, Strockbine L, Park LS, VandenBos T, Zappone JD, Painter SL, Armitage RJ (1997). "Molecular characterization of the human interleukin (IL)-17 receptor". Cytokine. 9 (11): 794–800. doi:10.1006/cyto.1997.0240. PMID 9367539.
  3. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J (2006). "Cutting edge: interleukin 17 signals through a heteromeric receptor complex". J. Immunol. 177 (1): 36–9. doi:10.4049/jimmunol.177.1.36. PMID 16785495.
  4. Tian E, Sawyer JR, Largaespada DA, Jenkins NA, Copeland NG, Shaughnessy JD (2000). "Evi27 encodes a novel membrane protein with homology to the IL17 receptor". Oncogene. 19 (17): 2098–109. doi:10.1038/sj.onc.1203577. PMID 10815801.
  5. Shi Y, Ullrich SJ, Zhang J, Connolly K, Grzegorzewski KJ, Barber MC, Wang W, Wathen K, Hodge V, Fisher CL, Olsen H, Ruben SM, Knyazev I, Cho YH, Kao V, Wilkinson KA, Carrell JA, Ebner R (2000). "A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity". J. Biol. Chem. 275 (25): 19167–76. doi:10.1074/jbc.M910228199. PMID 10749887.
  6. Lee J, Ho WH, Maruoka M, Corpuz RT, Baldwin DT, Foster JS, Goddard AD, Yansura DG, Vandlen RL, Wood WI, Gurney AL (2001). "IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1". J. Biol. Chem. 276 (2): 1660–4. doi:10.1074/jbc.M008289200. PMID 11058597.
  7. Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L, Kragballe K (February 2009). "Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin". Br. J. Dermatol. 160 (2): 319–24. doi:10.1111/j.1365-2133.2008.08902.x. PMID 19016708.
  8. Wu B, Jin M, Zhang Y, Wei T, Bai Z (July 2011). "Evolution of the IL17 receptor family in chordates: a new subfamily IL17REL". Immunogenetics. 63 (12): 835–45. doi:10.1007/s00251-011-0554-4. PMID 21732179.
  9. Gaffen SL (August 2009). "Structure and signalling in the IL-17 receptor family". Nat. Rev. Immunol. 9 (8): 556–67. doi:10.1038/nri2586. PMC 2821718. PMID 19575028.
  10. 10.0 10.1 10.2 10.3 10.4 Ho AW, Gaffen SL (March 2010). "IL-17RC: a partner in IL-17 signaling and beyond". Semin Immunopathol. 32 (1): 33–42. doi:10.1007/s00281-009-0185-0. PMC 2837117. PMID 20012905.

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