Key Points
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
Each of the many different cell types of the immune system expresses one or several activating receptors which serve a central role in the cell's surveillance function. Many of these cell-surface receptors share a distinctive modular design that consists of a ligand-binding module with no intrinsic signalling capability that is non-covalently associated with one or more dimeric signalling modules. Receptor assembly is directed by unique polar contacts within the transmembrane domains, whereas extracellular contacts can contribute to stability and specificity. This Review discusses the structural basis of receptor assembly and the implications of these findings for the mechanisms of receptor triggering.
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Acknowledgements
This work was supported by the National Institutes of Health (RO1 AI054,520 to K.W.W.). We would like to thank our co-workers who contributed to these studies, J.R. Schnell, J.J. Chou, J. Pyrdol, J. Feng, D. Garrity and C. Xu. We would also like to thank M.J. Call for helpful discussions and for help in preparing the original figures.
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Glossary
- Immunoglobulin superfamily
-
A large group of proteins that are built on a common fold called the immunoglobulin fold, which is composed of a sandwich of two β-sheets that is stabilized by a disulfide bond.
- C-type lectin family
-
A large group of proteins that share a characteristic double-loop fold stabilized by two highly conserved disulfide bonds.
- Immunoreceptor tyrosine based activation motif
-
(ITAM). Cytoplasmic sequences containing tyrosine residues that recruit SRC homology 2 (SH2)-domain-containing kinases when phosphorylated; consensus sequence is (YXXI/L)X[6-8](YXXI/L) (where X is any amino acid).
- Endoplasmic reticulum microsomes
-
Endoplasmic-reticulum-derived membrane vesicles that contain all components necessary for membrane and secretory protein biosynthesis, isolated from whole cell homogenates by density fractionation.
- Type I and II membrane proteins
-
These proteins span the membrane only once and are classified by whether the N-terminus is found in the extracellular/lumenal space (type I) or in the cytosol (type II).
- Schiff base
-
A functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group; in this case it forms part of the light-sensing chromophore (retinal) that is used by the light-driven proton pump bacteriorhodopsin.
- Catalytic water
-
In this context (aspartyl proteases), the water molecule that is bound by the enzyme active site and used to initiate peptide bond hydrolysis.
- Immunoreceptor tyrosine-based inhibitory motif
-
(ITIM). Cytoplasmic sequences containing tyrosine residues that recruit (SH2)-domain-containing phosphatases when phosphorylated; consensus sequence is (L/V/I/S/T)XYXX(L/V) (where X is any amino acid).
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Call, M., Wucherpfennig, K. Common themes in the assembly and architecture of activating immune receptors. Nat Rev Immunol 7, 841–850 (2007). https://doi.org/10.1038/nri2186
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DOI: https://doi.org/10.1038/nri2186
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