This webpage will investigate the structure of LAT and identify conserved regions between different species. We will also explore how different proteins interact with various amino acid residues in LAT to transduce signals. There will be a brief discussion of LAT2/LAB as well. These pieces of information will relate LAT structure to its biological function.

LAT, named after “linker for activation of T-cells”, are type III, single-pass transmembrane proteins expressed in T-cells, NK cells, mast cells and platelets, but not in mature B-cells [1,2]. In humans, LAT has 4 different isoforms created by alternative splicing. As its name suggests, LAT functions as an adapter to integrate different downstream signaling proteins in an activated complex in immune cells [2]. LAT plays important roles in cell signaling pathways mediated by immunoreceptor tyrosine activating motif (ITAM) bearing receptors [2]. This webpage will focus on T-cell receptor (TcR) pathways although there are other pathways that also involve LAT. A simplified diagram of a TcR pathway with LAT is shown in figure 1.

Figure 1: T-cell receptor (TcR) signaling pathway involving LAT [3]. TcR is associated with CD3 chains with immunoreceptor tyrosine activating motifs (ITAMs). Downstream effector proteins of interest are PLC-γ1, GADS and Grb2. P = phosphorylated tyrosines. Image taken from Jerome,K.R. (2008). “Viral modulation of T-cell Receptor Signaling” J. Virol.82(9): 4194-4204. Original figure 1: TcR signaling.

In figure 1, activation of TcR by antigen peptide-MHC combination leads to phosphorylation of tyrosine residues in the ITAMs of the associated CD3 chains. Phosphorylated tyrosines on CD3 activate the tyrosine kinase ZAP-70 which phosphorylates specific tyrosine residues on LAT. LAT has no enzymatic function but the phosphorylated tyrosines on LAT acts as binding sites to recruit the downstream signaling proteins phospholipase C gamma 1 (PLC-γ1), Grb2-related adapter protein (GADS) and growth factor receptor-bound protein 2 (Grb2) [2]. This localizes the proteins into an activated signaling complex near the membrane. Subsequently, activated effector proteins transduce signals that result in the activation of different transcription factors like Nuclear Factor Kappa B (NF-κB) and nuclear factor of activated T-cells (NFAT). These transcription factors activate gene transcription resulting in diverse cellular responses such as cytoskeletal rearrangement, cell proliferation and secretion of cytokines like interleukin-2 (IL-2) [4]. Multiple sequence alignment data between mouse, rat and human LAT show 9 conserved tyrosine residues that can be phosphorylated [5]. The transmembrane domain and the palmitoylated juxtamembrane cysteine residues C26 and C29 are essential for proper localization of LAT [4,6]. There is also evidence that LAT can be further regulated by phosphorylation at serine(S)/threonine(T) residues [7]. LAT knockout mice show defective T-cell development while mutant mice with phenylalanines substituting for tyrosines in LAT develop a fatal lymphoproliferative disease [1,8]. Mutant cell lines expressing a cytosolic form of LAT are also deficient in TcR signaling [6]. These results indicate the importance of different structural features of LAT for proper signal transduction.

Another protein called LAT2 or Linker for activation of B-cells (LAB) is similar in structure and function to LAT although it has a very different primary sequence. LAT2 is expressed in B-cells but not in resting T-cells [9]. The role of LAT2 in B-cells is analogous to LAT in T-cells, suggesting transmembrane linker proteins are important components of lymphocyte signaling pathways [9].

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