Mechanism of membrane protein complex assembly

Accurate biogenesis of multi-subunit membrane protein complexes is vital for human health, with improper assembly of specific complexes associated with diverse diseases. Despite their critical roles in human physiology, our understanding of how these complexes assemble is still limited. I intend to address this knowledge gap in my independent career, contributing fundamental insights into basic biology with important implications for translational science. I will study the assembly of the human T-cell receptor, as a foundational paradigm for my career. T-cell receptors play essential roles in fighting pathogens, preventing autoimmunity, and developing personalised medicines, each of which relies on precisely controlled receptor assembly. Although downstream signalling pathways have been thoroughly characterised, how the T-cell receptor assembles from eight uncoordinatedly produced cognate subunits with accurate timing and stoichiometry remains elusive. Using a combination of cell-free and in cell approaches, I aim to identify and characterise key factors required for assembly of the T-cell receptor, providing comprehensive insights into the assembly pathway. This proposal not only lays the foundation for understanding general principles of membrane protein complex assembly but also offers perspective on exploring the therapeutic potential of targeting assembly pathways.