Biology:Immunoreceptor tyrosine-based activation motif

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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.[1] 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.[2][3]

Structure

The motif contains a tyrosine separated from a leucine or isoleucine by any two other amino acids, giving the signature YxxL/I.[1] 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).[4][5][6]

Function

The T-cell receptor complex with TCR-α and TCR-β chains, CD3 and ζ-chain accessory molecules. ITAMs are represented in blue on the tails of the CD3 subunits.

ITAMs are important for signal transduction, mainly in immune cells. They are found in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors[7] 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.[1][7] 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.[8][9][10] 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.[11][12][13]

Genetic variations

Rare human genetic mutations are catalogued in the human genetic variation databases[14][15][16] which can reportedly result in creation or deletion of ITIM and ITAMs.[17]

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

References

  1. ↑ 1.0 1.1 1.2 Abbas, Abul K; Lichtman, Andrew H. (2009), Basic Immunology: Functions and Disorders of the Immune System (3 ed.), Philadelphia, PA: Saunders, ISBN 978-1-4160-4688-2 
  2. ↑ 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. doi:10.1359/JBMR.051016. ISSN 0884-0431. PMID 16418779. https://escholarship.org/content/qt4nh8649t/qt4nh8649t.pdf?t=lnq1ht. 
  3. ↑ Paloneva, Juha; Mandelin, Jami; Kiialainen, Anna; Böhling, Tom; Prudlo, Johannes; Hakola, Panu; Haltia, Matti; Konttinen, Yrjö T. et al. (2003-08-18). "DAP12/TREM2 Deficiency Results in Impaired Osteoclast Differentiation and Osteoporotic Features" (in en). Journal of Experimental Medicine 198 (4): 669–675. doi:10.1084/jem.20030027. ISSN 0022-1007. PMID 12925681. 
  4. ↑ Rogers, Neil C.; Slack, Emma C.; Edwards, Alexander D.; Nolte, Martijn A.; Schulz, Oliver; Schweighoffer, Edina; Williams, David L.; Gordon, Siamon et al. (April 2005). "Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins". Immunity 22 (4): 507–517. doi:10.1016/j.immuni.2005.03.004. ISSN 1074-7613. PMID 15845454. 
  5. ↑ 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. doi:10.1182/blood-2005-03-1239. ISSN 0006-4971. PMID 15956283. 
  6. ↑ Suzuki-Inoue, Katsue; Fuller, Gemma L. J.; García, Angel; Eble, Johannes A.; Pöhlmann, Stefan; Inoue, Osamu; Gartner, T. Kent; Hughan, Sascha C. et al. (2006-01-15). "A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2". Blood 107 (2): 542–549. doi:10.1182/blood-2005-05-1994. ISSN 0006-4971. PMID 16174766. 
  7. ↑ 7.0 7.1 "Non-catalytic tyrosine-phosphorylated receptors". Immunological Reviews 250 (1): 258–76. November 2012. doi:10.1111/imr.12008. PMID 23046135. 
  8. ↑ Pasquier, Benoit; Launay, Pierre; Kanamaru, Yutaka; Moura, Ivan C.; Pfirsch, Séverine; Ruffié, Claude; Hénin, Dominique; Benhamou, Marc et al. (January 2005). "Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM". Immunity 22 (1): 31–42. doi:10.1016/j.immuni.2004.11.017. ISSN 1074-7613. PMID 15664157. 
  9. ↑ O’Neill, Shannon K.; Getahun, Andrew; Gauld, Stephen B.; Merrell, Kevin T.; Tamir, Idan; Smith, Mia J.; Dal Porto, Joseph M.; Li, Quan-Zhen et al. (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. doi:10.1016/j.immuni.2011.10.011. ISSN 1074-7613. PMID 22078222. 
  10. ↑ Pfirsch-Maisonnas, Séverine; Aloulou, Meryem; Xu, Ting; Claver, Julien; Kanamaru, Yutaka; Tiwari, Meetu; Launay, Pierre; Monteiro, Renato C. et al. (2011-04-19). "Inhibitory ITAM Signaling Traps Activating Receptors with the Phosphatase SHP-1 to Form Polarized "Inhibisome" Clusters" (in en). Science Signaling 4 (169): ra24. doi:10.1126/scisignal.2001309. ISSN 1945-0877. PMID 21505186. https://www.science.org/doi/10.1126/scisignal.2001309. 
  11. ↑ Long, Eric O. (August 2008). "Negative signaling by inhibitory receptors: the NK cell paradigm". Immunological Reviews 224: 70–84. doi:10.1111/j.1600-065X.2008.00660.x. ISSN 1600-065X. PMID 18759921. 
  12. ↑ 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" (in en). Journal of Innate Immunity 6 (6): 727–738. doi:10.1159/000363449. ISSN 1662-811X. PMID 25033984. 
  13. ↑ Ligeti, E.; Csépányi-Kömi, R.; Hunyady, L. (April 2012). "Physiological mechanisms of signal termination in biological systems". Acta Physiologica 204 (4): 469–478. doi:10.1111/j.1748-1716.2012.02414.x. ISSN 1748-1716. PMID 22260256. https://pubmed.ncbi.nlm.nih.gov/22260256/. 
  14. ↑ "A global reference for human genetic variation". Nature 526 (7571): 68–74. October 2015. doi:10.1038/nature15393. PMID 26432245. Bibcode: 2015Natur.526...68T. 
  15. ↑ "dbSNP: the NCBI database of genetic variation". Nucleic Acids Research 29 (1): 308–11. January 2001. doi:10.1093/nar/29.1.308. PMID 11125122. 
  16. ↑ "Transcript expression-aware annotation improves rare variant interpretation". Nature 581 (7809): 452–458. May 2020. doi:10.1038/s41586-020-2329-2. PMID 32461655. Bibcode: 2020Natur.581..452C. 
  17. ↑ "TraPS-VarI: Identifying genetic variants altering phosphotyrosine based signalling motifs". Scientific Reports 10 (1): 8453. May 2020. doi:10.1038/s41598-020-65146-2. PMID 32439998. Bibcode: 2020NatSR..10.8453U. 



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