Membrane-Based Assembly and Interactions in Immune Receptors

Immune receptors are modular sensors that detect molecular changes indicating infection, cell/tissue damage, oncogenic transformation, or exposure to allergens, and the signals they transmit initiate and regulate immune responses. These transmembrane receptors are often composed of one or more single-spanning membrane proteins and are modular in two important aspects. First, many immune receptors assemble from ligand-binding modules and signaling modules made up of separate proteins that come together during biosynthesis or upon activation through specific transmembrane domain (TMD) interactions. Second, the assembled receptor complexes comprise extracellular modules (structured protein domains) that interact with their environments and intracellular modules (often intrinsically unstructured domains) that read out these interactions biochemically. These are connected by and must communicate through the receptor TMDs. Here we review the molecular principles and structural motifs that organize and regulate immune receptors in the lipid bilayer with a view to understanding both how they are built and what roles the molecular interactions with and within the membrane play in their structures and functions. We focus primarily on examples where biochemical and structural data reveal highly specific interactions and show how these represent solutions that appear repeatedly across receptor families and can be exploited in synthetic biology applications.