Immunoreceptor tyrosine-based activation motif explained

An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors, cell-surface proteins found mainly on immune cells. Its major role is being an integral component for the initiation of a variety of signaling pathway and subsequently the activation of immune cells, although different functions have been described, for example an osteoclast maturation.[1] [2]

Structure

The motif contains a tyrosine separated from a leucine or isoleucine by any two other amino acids, giving the signature YxxL/I. Two of these signatures are typically separated by between 6 and 8 amino acids in the cytoplasmic tail of the molecule (YxxL/Ix(6-8)YxxL/I). However, it is worth noting that in various sources, this consensus sequence differs, mainly in the number of amino acids between individual signatures. Apart from ITAMs which have the structure described above, there is also a variety of proteins containing ITAM-like motifs, which have a very similar structure and function (for example in Dectin-1 protein).[3] [4] [5]

Function

ITAMs are important for signal transduction, mainly in immune cells. They are found in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors[6] such as the CD3 and ζ-chains of the T cell receptor complex, the CD79-alpha and -beta chains of the B cell receptor complex, and certain Fc receptors.[6] The tyrosine residues within these motifs become phosphorylated by Src family kinases following interaction of the receptor molecules with their ligands. Phosphorylated ITAMs serve as docking sites for other proteins containing a SH2 domain, usually two domains in tandem, inducing a signaling cascade mediated by Syk family kinases (which are the primary proteins that bind to phosphorylated ITAMs), namely either Syk or ZAP-70, resulting mostly in the activation of given cell. Paradoxically, in some cases, ITAMs and ITAM-like motifs do not have an activating effect, but rather an inhibitory one.[7] [8] [9] Exact mechanisms of this phenomenon are as of yet not elucidated.

Other non-catalytic tyrosine-phosphorylated receptors carry a conserved inhibitory motif (ITIM) that, when phosphorylated, results in the inhibition of the signaling pathway via recruitment of phosphatases, namely SHP-1, SHP-2 and SHIP1. This serves not only for inhibition and regulation of signalling pathways related to ITAM-based signalling, but also for termination of signalling.[10] [11] [12]

Genetic variations

Rare human genetic mutations are catalogued in the human genetic variation databases[13] [14] [15] which can reportedly result in creation or deletion of ITIM and ITAMs.[16]

Examples

Examples shown below list both proteins that contain the ITAM themselves and proteins that use ITAM-based signalling with the help of associated proteins which contain the motif.

CD3γ, CD3δ, CD3ε, TYROBP (DAP12), FcαRI, FcγRI, FcγRII, FcγRIII, Dectin-1, CLEC-1, CD28, CD72

Notes and References

  1. Humphrey. Mary Beth. Daws. Michael R.. Spusta. Steve C.. Niemi. Eréne C.. Torchia. James A.. Lanier. Lewis L.. Seaman. William E.. Nakamura. Mary C.. February 2006. TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. Journal of Bone and Mineral Research. 21. 2. 237–245. 10.1359/JBMR.051016. 0884-0431. 16418779. 34957715.
  2. Paloneva. Juha. Mandelin. Jami. Kiialainen. Anna. Böhling. Tom. Prudlo. Johannes. Hakola. Panu. Haltia. Matti. Konttinen. Yrjö T.. Peltonen. Leena. 2003-08-18. DAP12/TREM2 Deficiency Results in Impaired Osteoclast Differentiation and Osteoporotic Features. Journal of Experimental Medicine. en. 198. 4. 669–675. 10.1084/jem.20030027. 12925681. 2194176. 0022-1007. free.
  3. Rogers. Neil C.. Slack. Emma C.. Edwards. Alexander D.. Nolte. Martijn A.. Schulz. Oliver. Schweighoffer. Edina. Williams. David L.. Gordon. Siamon. Tybulewicz. Victor L.. Brown. Gordon D.. Reis e Sousa. Caetano. April 2005. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 22. 4. 507–517. 10.1016/j.immuni.2005.03.004. 1074-7613. 15845454. free.
  4. Underhill. David M.. Rossnagle. Eddie. Lowell. Clifford A.. Simmons. Randi M.. 2005-10-01. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 106. 7. 2543–2550. 10.1182/blood-2005-03-1239. 0006-4971. 1895265. 15956283.
  5. Suzuki-Inoue. Katsue. Fuller. Gemma L. J.. García. Angel. Eble. Johannes A.. Pöhlmann. Stefan. Inoue. Osamu. Gartner. T. Kent. Hughan. Sascha C.. Pearce. Andrew C.. Laing. Gavin D.. Theakston. R. David G.. 2006-01-15. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. 107. 2. 542–549. 10.1182/blood-2005-05-1994. 0006-4971. 16174766. 168505 .
  6. Dushek O, Goyette J, van der Merwe PA . Non-catalytic tyrosine-phosphorylated receptors . Immunological Reviews . 250 . 1 . 258–76 . November 2012 . 23046135 . 10.1111/imr.12008 . 1549902 .
  7. Pasquier. Benoit. Launay. Pierre. Kanamaru. Yutaka. Moura. Ivan C.. Pfirsch. Séverine. Ruffié. Claude. Hénin. Dominique. Benhamou. Marc. Pretolani. Marina. Blank. Ulrich. Monteiro. Renato C.. January 2005. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity. 22. 1. 31–42. 10.1016/j.immuni.2004.11.017. 1074-7613. 15664157. free.
  8. O’Neill. Shannon K.. Getahun. Andrew. Gauld. Stephen B.. Merrell. Kevin T.. Tamir. Idan. Smith. Mia J.. Dal Porto. Joseph M.. Li. Quan-Zhen. Cambier. John C.. 2011-11-23. Monophosphorylation of CD79a and b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity. 35. 5. 746–756. 10.1016/j.immuni.2011.10.011. 1074-7613. 3232011. 22078222.
  9. Pfirsch-Maisonnas. Séverine. Aloulou. Meryem. Xu. Ting. Claver. Julien. Kanamaru. Yutaka. Tiwari. Meetu. Launay. Pierre. Monteiro. Renato C.. Blank. Ulrich. 2011-04-19. Inhibitory ITAM Signaling Traps Activating Receptors with the Phosphatase SHP-1 to Form Polarized "Inhibisome" Clusters. Science Signaling. en. 4. 169. ra24. 10.1126/scisignal.2001309. 1945-0877. 21505186. 206670699. subscription.
  10. Long. Eric O.. August 2008. Negative signaling by inhibitory receptors: the NK cell paradigm. Immunological Reviews. 224. 70–84. 10.1111/j.1600-065X.2008.00660.x. 1600-065X. 2587243. 18759921.
  11. Kane. Barry A.. Bryant. Katherine J.. McNeil. H. Patrick. Tedla. Nicodemus T.. 2014. Termination of Immune Activation: An Essential Component of Healthy Host Immune Responses. Journal of Innate Immunity. en. 6. 6. 727–738. 10.1159/000363449. 1662-811X. 25033984. 6741560. free.
  12. Ligeti. E.. Csépányi-Kömi. R.. Hunyady. L.. April 2012. Physiological mechanisms of signal termination in biological systems. Acta Physiologica. 204. 4. 469–478. 10.1111/j.1748-1716.2012.02414.x. 1748-1716. 22260256. 13455093.
  13. Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR . 6 . A global reference for human genetic variation . Nature . 526 . 7571 . 68–74 . October 2015 . 26432245 . 4750478 . 10.1038/nature15393 . 2015Natur.526...68T .
  14. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K . dbSNP: the NCBI database of genetic variation . Nucleic Acids Research . 29 . 1 . 308–11 . January 2001 . 11125122 . 29783 . 10.1093/nar/29.1.308 .
  15. Cummings BB, Karczewski KJ, Kosmicki JA, Seaby EG, Watts NA, Singer-Berk M, Mudge JM, Karjalainen J, Satterstrom FK, O'Donnell-Luria AH, Poterba T, Seed C, Solomonson M, Alföldi J, Daly MJ, MacArthur DG . 6 . Transcript expression-aware annotation improves rare variant interpretation . Nature . 581 . 7809 . 452–458 . May 2020 . 32461655 . 7334198 . 10.1038/s41586-020-2329-2 . 2020Natur.581..452C .
  16. Ulaganathan VK . TraPS-VarI: Identifying genetic variants altering phosphotyrosine based signalling motifs . Scientific Reports . 10 . 1 . 8453 . May 2020 . 32439998 . 7242328 . 10.1038/s41598-020-65146-2 . 2020NatSR..10.8453U .

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