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 of abnormal cells or structures and the initiation of an immune response. These transmembrane receptors are not grouped into the NTR family based on sequence homology, but because they share a conserved signaling pathway utilizing the same signaling motifs. A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation. For that tyrosine residues in the cytoplasmic tail of the receptors have to be phosphorylated, hence the receptors are referred to as tyrosine-phosphorylated receptors. They are called non-catalytic receptors, as the receptors have no intrinsic tyrosine kinase activity and cannot phosphorylate their own tyrosine residues. Phosphorylation is mediated by additionally recruited kinases. A prominent member of this receptor family is the T-cell receptor.
Features and Classification Members of the Non-catalytic tyrosine-phosphorylated receptor family share a couple of common features. The most prominent feature is the presence of conserved signaling motifs containing tyrosine residue, such as Immunoreceptor tyrosine-based activation motifs (ITAMs), in the cytoplasmic tail of the receptors. The receptor signaling pathway is initiated by ligand binding to the extracellular domains of the receptor. Upon binding, the tyrosine residues in the signaling motifs are phosphorylated by membrane-associated tyrosine kinases. The receptors themselves have no intrinsic tyrosine kinase activity. The phosphorylated NTRs, in turn, initiate a specific intracellular signaling cascades. The signaling cascade is down-regulated by dephosphorylation by protein tyrosine phosphatases. Additional characteristics of the receptor family are a rather small (< 20 nm) extracellular domain and the binding to ligands that are anchored to solid surfaces or membranes of other cells. NTRs are exclusively expressed in leukocytes. Based on those features, about 100 distinct NTRs have been identified. The table below lists different classes of NTRs. Members of a class have a high sequence homology and typically share the same gene locus.
Structure NTRs are transmembrane glycoproteins with typically small ectodomains of 6 to 10 nm. NTRs have either an N-terminal or C terminal ectodomains. Ectodomains have a high sequence diversity between members. Many NTRs have an unstructured intracellular domain which contains tyrosine residues that can be phosphorylated by tyrosine kinases. Some receptors in this family, however, lack a cytoplasmic tail and therefore associate with adaptor proteins containing the same tyrosine residues. Adaptor proteins associate to their respective NTR through their transmembrane helixes carrying oppositely charged residues. The cytoplasmic domains do not contain any intrinsic tyrosine kinase activity.
Conserved tyrosine-containing motifs Tyrosine residues of NTRs mostly appear in conserved amino acid motifs with defined sequence signatures that define whether the receptor plays an activator or inhibiting role in the cell. These motifs allow binding of proteins containing a SH2 domain. Motifs are intrinsic or in the associated adaptor subunits. Immunoreceptor tyrosine-based activation motifs (ITAMs) are short amino acid sequences that contain two tyrosine residues (Y) arranged as Yxx(L/I)x6-8Yxx(L/I), where L and I indicate Leucine or Isoleucine residue respectively (according to amino acid abbreviations), x denotes any amino acids, a subscribe 6-8 indicates a sequence of 6 to 8 amino acids in length. ITAMs recruits activating kinases to the NTR. Inhibitory signals are transduced by Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of the signature (S/I/V/L)xYxx(I/V/L), bind to cytoplasmic tyrosine phosphatases. Immunoreceptor Tyrosine-based Switch Motifs (ITSMs) with the signature TxYxx(I/V) may induce both activator and inhibitory signals. These motifs are confined to SLAM family receptors. Finally, Immunoglobulin Tail Tyrosine Motifs (ITTMs) with a YxNM signature have been found to have a costimulatory effect.
Signalling Pathway
Biophysics of receptor-ligand binding The signalling pathway of an NTR is induced upon binding to its respective ligand. NTRs, as they are defined, have a short ectodomain (5 - 10 nm) and bind to surface-anchored ligands. For binding to take place, the membrane of the leukocyte has to come into close proximity to the surface with the ligand. The receptor-ligand complex, once bound, spans a dimension of about 10-16 nm. Ectodomains of other surface molecules can be much larger (up to 50 nm), therefore the membrane has to bend towards the ligand, which introduces tension within the membrane. Additionally, large pulling forces can act on the complex, changing dissociation rates of the complex.
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