Receptors that are constructed from single-spanning membrane protein subunits rely on specific transmembrane (TM) interactions to establish their oligomeric structures and transmit conformational changes that govern signalling through the plasma membrane, but few have yielded to efforts to understand these mechanisms from a structural perspective. One of the most complex of these receptors, the T cell antigen receptor (TCR), is an octameric membrane protein assembly that plays a central role in adaptive immunity by driving T lymphocyte responses. In recent work1 examining the role of membrane-embedded sequences in TCR assembly and structure, we have combined solution NMR analysis, intra-membrane disulphide scanning and molecular dynamics (MD) simulations to identify an evolutionarily conserved TCRαβ coiled-coil TM arrangement that forms a structured hub for the receptor complex within the membrane. Mutations designed to perturb this core structure resulted in defective assembly and reduced receptor complex stability, demonstrating that the requirements for highly specific interactions among subunit TM domains are much more stringent than previously thought. We are now expanding this combined biophysical, biochemical and computational approach to interrogate all TM interfaces within the fully assembled receptor complex and developing cellular systems to probe the functional consequences of alterations in these interfaces.