Current Topic pubs.acs.org/biochemistry
Modular Activating Receptors in Innate and Adaptive Immunity Richard Berry*,†,‡ and Matthew E. Call*,§,∥ †
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia ‡ ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia § Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia ∥ Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia ABSTRACT: Triggering of cell-mediated immunity is largely dependent on the recognition of foreign or abnormal molecules by a myriad of cell surface-bound receptors. Many activating immune receptors do not possess any intrinsic signaling capacity but instead form noncovalent complexes with one or more dimeric signaling modules that communicate with a common set of kinases to initiate intracellular information-transfer pathways. This modular architecture, where the ligand binding and signaling functions are detached from one another, is a common theme that is widely employed throughout the innate and adaptive arms of immune systems. The evolutionary advantages of this highly adaptable platform for molecular recognition are visible in the variety of ligand−receptor interactions that can be linked to common signaling pathways, the diversification of receptor modules in response to pathogen challenges, and the amplification of cellular responses through incorporation of multiple signaling motifs. Here we provide an overview of the major classes of modular activating immune receptors and outline the current state of knowledge regarding how these receptors assemble, recognize their ligands, and ultimately trigger intracellular signal transduction pathways that activate immune cell effector functions.
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responsible for the ultimate functional outcomes of immune cell activation. Because extracellular ligand binding and intracellular signaling functions are encoded by separate genes, this modular design creates a platform in which receptors can rapidly evolve new ligand specificities, associate with multiple signaling modules, and even exchange one signaling pathway for another through relatively small changes. In some cases, this functional diversification has clearly been driven by the selective pressures of pathogen immune-evasion strategies (see Natural Killer Cell Receptors). This flexibility is facilitated by the fact that the molecular interactions governing the assembly of these modules into functional receptors are largely restricted to their transmembrane (TM) domains, where very minimal sequence motifs, in most cases a single basic (lysine or arginine) residue in the ligand-binding subunits, can mediate stable assembly with a signaling module within the lipid bilayer, requiring little or no contribution from extracellular or intracellular sequences. In the most complex of the modular activating immune receptors, the T cell antigen receptor (TCR) assembles with three different dimeric signaling modules simultaneously,
he mammalian immune system employs a staggering array of cell surface and intracellular sensors to guide responses to infected or transformed cells that pose a danger to the host. The evolutionary challenge of developing and maintaining an arsenal of receptors capable of responding to a rapidly changing universe of pathogens while sparing normal host tissues is a formidable one, and the systems that have arisen to meet this challenge are correspondingly complex and multifaceted. A large proportion of the receptors that most directly control primary immune effector functions (arming and clonal expansion of T and B lymphocytes, activation of killer cells, and secretion of cytokines and antibodies) belong to a broad class of “modular” activating immune receptors, also known as multisubunit immune-recognition receptors (MIRRs). These receptors share a distinctive molecular architecture in which a variety of ligand-recognition modules assemble noncovalently with one or more of a small group of dimeric signal-transducing modules to form functional membrane-embedded receptor complexes (Figure 1).1 In contrast to the receptor tyrosine kinase and cytokine receptor families, these signal-transducing modules neither encode nor constitutively associate with any enzymatic activity but rather couple to intracellular biochemical pathways through cytosolic tyrosine-based motifs that become targets of Src-family kinases upon binding of stimulatory ligands. In their phosphorylated form, these sequences recruit additional signaling molecules that activate the pathways © XXXX American Chemical Society
Received: December 22, 2016 Revised: January 30, 2017
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DOI: 10.1021/acs.biochem.6b01291 Biochemistry XXXX, XXX, XXX−XXX
Current Topic
Biochemistry
Figure 1. Schematic representation of the main modular activating immune receptors and their ligands. Noncolored ovals indicate domains whose presence varies in different members of a particular receptor family. An asterisk indicates receptor families in which at least one member may associate with a signaling adaptor different from the one depicted.
receptors from different protein families,1 and they share with the more restricted DAP10 signaling module a lack of folded extracellular domains. These are predominantly homodimeric and contain stabilizing intermolecular disulfide bonds. In contrast, the CD3 and CD79 modules associate exclusively with the variable T and B cell antigen receptors, respectively, and form heterodimers through interactions between their single extracellular immunoglobulin (Ig) domains. The cytosolic Syk/ZAP70-binding immunoreceptor tyrosine-based activation motif (ITAM)3 appears in all but DAP10, which instead contains a PI3 kinase (PI3K) and Grb2 recruiting motif.4−6 Here, we group these proteins according to their evolutionary relationships as we briefly describe what is known about their structures and signaling features. ζ and FcRγ. The ζ chain was first identified as a component of the mouse and human T cell antigen receptor (TCR)−CD3 complexes in the form of a disulfide-linked ζζ homodimer.7,8 It is therefore often termed TCRζ or CD3ζ, though its sequence, structure, and genomic location are not closely related to either TCR or CD3 genes9 and the protein has been given its own CD designation (CD247). It also serves as a signaling module for several different innate lymphocyte receptors (see below). The ζ chain contains only a small, nine-amino acid extracellular region and dimerizes through its single α-helical TM domain,10
endowing it with exceptional sensitivity due, in part, to the large number of coupled signaling motifs. Importantly, this class of receptors represents the key conceptual template for a rapidly developing group of cancer immunotherapy approaches that are based on reengineering immune signaling platforms to endow immune cells with enhanced tumor-recognition and -destruction capabilities.2 Understanding how the naturally evolved versions assemble, bind to ligands, and transmit signals may therefore provide an improved set of design principles to guide future generations of these promising technologies. Here we review the major classes of modular activating receptors that are utilized by immune cells and summarize what is known about how they are built, the ligands they recognize, how these ligands are bound (in cases in which structures are available), and some current views about how signaling is initiated. We begin with a description of the signaling modules.
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DEFINING FEATURES OF THE SIGNALING MODULES Modular activating immune receptors incorporate one or more of seven different dimeric signaling modules (Figure 2). Three of these (ζ, FcRγ, and DAP12) are employed by many B
DOI: 10.1021/acs.biochem.6b01291 Biochemistry XXXX, XXX, XXX−XXX
Current Topic
Biochemistry
Figure 2. Key features of the signaling modules: (A) FcRγ and ζ chain homodimers, (B) DAP12 and DAP10 homodimers, (C) DAP12−NKG2C trimer, (D) CD3γε and CD3δε heterodimers, and (E) CD79αβ heterodimers. Intermolecular disulfide bonds are shown as black bars, and key polar residues discussed in the text are shown as red dots (aspartic/glutamic acid) and yellow dots (serine, threonine, and tyrosine). Cytoplasmic signaling motifs are represented as orange rectangles (ITAMs) and yellow rectangles (PI3K motif). For known structures, graphics were generated from PDB entries 2HAC [human ζζ TM dimer nuclear magnetic resonance (NMR) structure], 2L34 (human DAP12 TM dimer NMR structure), 2L35 (human DAP12−NKG2C TM trimer NMR structure), 1SY6 (human CD3γε crystal structure), 1XIW (human CD3δε crystal structure), and 3KHO (monomer from the mouse CD79β homodimer crystal structure).
observed as a heterodimer in some receptor systems. The two homodimers also appear to be interchangeable for some receptors in cell types that express both proteins, such as FcγRIIIA (CD16A) in natural killer cells. DAP12 and DAP10. Two independent homology searches for sequences with features similar to those of signaling subunits like ζ and FcRγ identified cDNAs encoding an apparent 12 kDa ITAM-containing protein in humans and mice, which were named DAP1215 and KARAP,16 respectively (we will use DAP12 here). DAP12 associates with a large number of activating receptors in both lymphoid and myeloid immune cells through a centrally located lysine residue in their TM domains.17 While the DAP12 protein is
