Folding speeds of helical membrane proteins.

Membrane proteins play key roles in human health, contributing to cellular signaling, ATP synthesis, immunity, and metabolite transport. Protein folding is the pivotal early step for their proper functioning. Understanding how this class of proteins adopts their native folds could potentially aid in drug design and therapeutic interventions for misfolding diseases. It is an essential piece in the whole puzzle to untangle their kinetic complexities, such as how rapid membrane proteins fold, how their folding speeds are influenced by changing conditions, and what mechanisms are at play. This review explores the folding speed aspect of multipass α-helical membrane proteins, encompassing plausible folding scenarios based on the timing and stability of helix packing interactions, methods for characterizing the folding time scales, relevant folding steps and caveats for interpretation, and potential implications. The review also highlights the recent estimation of the so-called folding speed limit of helical membrane proteins and discusses its consequent impact on the current picture of folding energy landscapes.