How to get a folded protein across a membrane

Several protein-targeting fields have recently converged in their observations of what once was thought to be a rare phenomenon: the transport of folded and oligomerized proteins across membranes. Three of the newly characterized pathways that are known to accommodate folded substrates are the peroxisomal targeting machinery for matrix proteins, the twin-arginine translocation (Tat) of bacteria and the related Delta pH-dependent pathway of plant plastids, and the cytoplasm-to-vacuole targeting (Cvt) pathway in Saccharomyces cerevisiae. Current work strives to understand the molecular mechanisms that accomplish transport of folded substrates. The aim of this commentary is to highlight our knowledge of transport mechanisms, point out areas for future research and address how paradigms of classical protein translocation have shaped current views.