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]

Contents

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-a and TCR-b chains, CD3 and z-chain accessory molecules. ITAMs are represented in blue on the tails of the CD3 subunits. TCRComplex.png
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

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<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

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<span class="mw-page-title-main">CD22</span> Lectin molecule

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An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acid serine, I is the amino acid isoleucine, and V is the amino acid valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response.

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<span class="mw-page-title-main">LYN</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">TYROBP</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CLEC7A</span> Protein-coding gene in humans

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<span class="mw-page-title-main">FCRL3</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CD79A</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">FCAR</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Killer activation receptor</span> Class of protein

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<span class="mw-page-title-main">CLEC6A</span> Protein-coding gene in humans

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References

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  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" (PDF). Journal of Bone and Mineral Research. 21 (2): 237–245. doi:10.1359/JBMR.051016. ISSN   0884-0431. PMID   16418779. S2CID   34957715.
  3. ↑ 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. 198 (4): 669–675. doi: 10.1084/jem.20030027 . ISSN   0022-1007. PMC   2194176 . PMID   12925681.
  4. ↑ 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. doi: 10.1016/j.immuni.2005.03.004 . ISSN   1074-7613. PMID   15845454.
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  6. ↑ 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. doi:10.1182/blood-2005-05-1994. ISSN   0006-4971. PMID   16174766. S2CID   168505.
  7. 1 2 Dushek O, Goyette J, van der Merwe PA (November 2012). "Non-catalytic tyrosine-phosphorylated receptors". Immunological Reviews. 250 (1): 258–76. doi:10.1111/imr.12008. PMID   23046135. S2CID   1549902.
  8. ↑ 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. 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; 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. doi:10.1016/j.immuni.2011.10.011. ISSN   1074-7613. PMC   3232011 . PMID   22078222.
  10. ↑ 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. 4 (169): ra24. doi:10.1126/scisignal.2001309. ISSN   1945-0877. PMID   21505186. S2CID   206670699.
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  15. ↑ Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (January 2001). "dbSNP: the NCBI database of genetic variation". Nucleic Acids Research. 29 (1): 308–11. doi:10.1093/nar/29.1.308. PMC   29783 . PMID   11125122.
  16. ↑ Cummings BB, Karczewski KJ, Kosmicki JA, Seaby EG, Watts NA, Singer-Berk M, et al. (May 2020). "Transcript expression-aware annotation improves rare variant interpretation". Nature. 581 (7809): 452–458. Bibcode:2020Natur.581..452C. doi:10.1038/s41586-020-2329-2. PMC   7334198 . PMID   32461655.
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