Common themes in the assembly and architecture of activating immune receptors

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Abstract
Activating receptors in the immune system serve critical surveillance functions, and most share a common modular architecture in which ligand-binding subunits and signalling subunits associate non-covalently to assemble functional receptor complexes. The mechanisms coupling extracellular ligand binding to intracellular signal initiation are not well understood, and this is largely due to a lack of information regarding the structure and molecular arrangement of subunits in intact receptor complexes. T-cell antigen receptor (TCR) comprises eight subunits that form four different dimers. Each of three signalling dimers assembles with the TCR through intramembrane contacts that require a specific basic residue in the transmembrane regions of the TCR and a pair of acidic residues in the transmembrane regions of the signalling dimer. Extracellular contacts also contribute stability and specificity to these associations. Other activating receptors expressed by natural killer (NK) cells, mast cells, macrophages, osteoclasts and platelets assemble using a similar intramembrane polar motif. These receptors derive from two evolutionarily unrelated protein families, indicating that this particular intramembrane assembly motif has independently arisen at least twice during evolution. Each signalling module has a preference for lysine or arginine and requires a particular placement of the basic residue relative to the membrane. The pair of acidic transmembrane residues in the ζζ signalling module packs closely in the interface and acts as a single structural unit to provide the binding site for the basic transmembrane residue from the TCR. Small changes in the transmembrane regions, such as the introduction of a basic transmembrane residue, can cause a receptor to couple to different signalling modules and thereby activate distinct intracellular pathways. There are specific mechanisms to ensure fidelity in the assembly process despite the apparent simplicity of this assembly motif. The number of dimeric signalling modules present in a complex is equal to the number of basic transmembrane residues in the receptor subunit. Therefore, by assembling into multimers or containing more than one basic transmembrane residue, different receptor system have evolved to couple to multiple signalling modules, which results in amplification of sensitivity to rare ligands and/or diversification of the cellular response by activating multiple signalling pathways. The ongoing mapping of structurally and functionally relevant intermolecular contacts within activating receptor complexes, will significantly advance our understanding of immune activation at the earliest stages and enhance the potential for therapeutic intervention.