REGULATION OF PROTEIN TOPOLOGY BY TRANS-ACTING FACTORS AT THE ENDOPLASMIC-RETICULUM

In mammalian cells, the Sec61 complex and translocating chain-associat ed membrane protein (TRAM) are necessary and sufficient to direct the biogenesis, in the appropriate topology, of all secretory and membrane proteins examined thus far. We demonstrate here that the proper trans location of the prion protein (PrP), a substrate that can be synthesiz ed in more than one topologic form, requires additional factors. In th e absence of these additional factors, PrP is synthesized exclusively in the transmembrane topology (termed the (PrP)-Pr-Ctm form) associate d with the development of neurodegenerative disease, Thus, translocati on accessory factors, acting on some but not other substrates, can fun ction as molecular switches to redirect nascent proteins toward diverg ent topologic fates with different functional consequences.