An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s that is repeated twice in the cytoplasmic tails of

non-catalytic tyrosine-phosphorylated receptors Non-catalytic tyrosine-phosphorylated receptors (NTRs), also called immunoreceptors or Src-family kinase-dependent receptors, are a group of cell surface receptors expressed by White blood cell, leukocytes that are important for cell migration and ...

, 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 An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...

maturation.

Structure

The motif contains a

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

separated from a

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

by any two other

s, 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, 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).

Function

ITAMs are important for signal transduction, mainly in immune cells. They are found in the cytoplasmic tails of non-catalytic tyrosine- phosphorylated receptors 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. The tyrosine residues within these motifs become phosphorylated by

Src family kinase Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src (gene), Src, YES1, Yes, FYN, Fyn, and FGR (gene), Fgr, forming the SrcA subfamily, Lck, HCK, Hck, Tyrosine-protein kinase BLK, Blk, and Lyn (Src fam ...

s following interaction of the receptor molecules with their

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

s. 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 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of Lymphocyte, lymphocytes (T cells, natural killer cells, and a subset of B cell, B cells). It is most prominently known to be recruited u ...

, 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. 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.

Genetic variations

Rare human genetic mutations are catalogued in the human genetic variation databases which can reportedly result in creation or deletion of ITIM and ITAMs.

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 CD28 (Cluster of Differentiation 28) is a protein expressed on T cells that provides essential co-stimulation, co-stimulatory signals required for T cell activation and survival. When T cells are stimulated through CD28 in conjunction with the T- ...

, CD72

References

{{DEFAULTSORT:Immunoreceptor Tyrosine-Based Activation Motif Cell signaling Immune system