Immunoreceptor tyrosine-based activation motif

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 on immune cells. It is an integral component for the initiation of the signaling pathway and subsequently the activation of immune cells.

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).

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 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 kinases (SFK) following interaction of the receptor molecules with their ligands. Phosphorylated ITAMs serve as docking sites for other proteins containing a SH2 domain inducing a signaling cascade resulting in the activation of the immune cell.

Other non-catalytic tyrosine-phosphorylated receptors carry a conserved inhibitory motif (ITIM) that, when phosphorylated, results in the inhibition of the signaling pathway.

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.