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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

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 leukocytes that are important for cell migration and the recognition ...

, cell-surface proteins found mainly on

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

. Its major role is being an integral component for the initiation of a variety of

signaling In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...

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 remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...

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 non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

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- ca ...

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 deprot ...

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, 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).

Function

ITAMs are important for signal transduction, mainly in immune cells. They are found in the cytoplasmic tails of non-catalytic tyrosine-

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

receptors such as the CD3 and

ζ-chain T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the ''CD247'' gene. Some older literature mention a similar protein called " ...

s of the

T cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...

complex, the

CD79 Introduction CD79 ( Cluster of Differentiation 79) is a transmembrane protein that forms a complex with the B-cell receptor (BCR) and generates a signal following recognition of antigen by the BCR. CD79 is composed of two distinct chains call ...

-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, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs ...

s following interaction of the receptor molecules with their

ligand In coordination chemistry, a ligand is an ion or molecule (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 electr ...

s. Phosphorylated ITAMs serve as docking sites for other proteins containing a

SH2 domain The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphory ...

, 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 Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...

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

, 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 ''Itim'' (Filipino for "black"), released overseas as ''The Rites of May'', is a 1976 Filipino thriller film and the directorial debut of Mike de Leon, with a screenplay by Clodualdo del Mundo Jr. and Gil Quito. The film stars Tommy Abuel as ...

) that, when phosphorylated, results in the inhibition of the signaling pathway via recruitment of phosphatases, namely

SHP-1 Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene. Function The protein encoded by this gene is a member ...

SHP-2 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...

and

SHIP1 Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the ''INPP5D'' gene in humans. SHIP1 is expressed predominantly ...

. 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 TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the ''TYROBP'' gene. Function This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation mo ...

(DAP12), FcαRI,

FcγRI CD64 (Cluster of Differentiation 64) is a type of integral membrane glycoprotein known as an Fc receptor that binds monomeric IgG-type antibodies with high affinity. It is more commonly known as Fc-gamma receptor 1 (FcγRI). After binding I ...

FcγRII CD32 (cluster of differentiation 32), also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc re ...

FcγRIII CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRI ...

, Dectin-1, CLEC-1,

CD28 CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...

CD72 CD7 (Cluster of Differentiation 7) is a protein that in humans is encoded by the ''CD7'' gene. Function This gene encodes a transmembrane protein which is a member of the immunoglobulin superfamily. This protein is found on thymocytes and matur ...

References

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