How to get a folded protein across a membrane

Several protein-targeting fields have recently converged in their observati ons of what once was thought to be a rare phenomenon: the transport of fold ed and oligomerized proteins across membranes. Three of the newly character ized pathways that are known to accommodate folded substrates are the perox isomal targeting machinery for matrix proteins, the twin-arginine transloca tion (Tat) of bacteria and the related Delta pH-dependent pathway of plant plastids, and the cytoplasm-to-vacuole targeting (Cvt) pathway in Saccharom yces cerevisiae. Current work strives to understand the molecular mechanism s that accomplish transport of folded substrates. The aim of this commentar y is to highlight our knowledge of transport mechanisms, point out areas fo r future research and address how paradigms of classical protein translocat ion have shaped current views.