Systematic identification of immunoreceptor tyrosine-based inhibitory motifs in the human proteome.

Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are short sequences of the consensus (ILV)-x-x-Y-x-(LV) in the cytoplasmic tail of immune receptors. The phosphorylation of tyrosines in ITIMs is known to be an important signalling mechanism regulating the activation of immune cells. The shortness of the motif makes it difficult to predict ITIMs in large protein databases. Simple pattern searches find ITIMs in approximately 30% of the protein sequences in the RefSeq database. The majority are false positive predictions. We propose a new database search strategy for ITIM-bearing transmembrane receptors based on the use of sequence context, i.e. the predictions of signal peptides, transmembrane helices (TMs) and protein domains. Our new protocol allowed us to narrow down the number of potential human ITIM receptors to 109 proteins (0.7% of RefPep). Of these, 36 have been described as ITIM receptors in the literature before. Many ITIMs are conserved between orthologous human and mouse proteins which represent novel ITIM receptor candidates. Publicly available DNA array expression data revealed that ITIM receptors are not exclusively expressed in blood cells. We hypothesise that ITIM signalling is not restricted to immune cells, but also functions in diverse solid organs of mouse and man.