Membrane protein folding is a fundamental yet poorly understood process in cell biology, despite membrane proteins comprising a substantial portion of cellular proteomes and playing critical roles in signaling, transport, and metabolism. Misfolding of these proteins underlies numerous diseases, making them important targets for therapeutic intervention. While pharmacological agents capable of correcting membrane protein misfolding have shown promise, their mechanisms of action and the early biogenesis of membrane proteins remain unclear. This dissertation addresses how polytopic membrane proteins are initially integrated into the lipid bilayer and begin folding. Understanding these early folding pathways is essential for elucidating disease mechanisms and for the rational design of therapies targeting misfolded membrane proteins or the cellular machinery that governs their biogenesis.
