Control of protein topology at the endoplasmic reticulum.

I have described recent work that supports several conclusions that might not have been previously expected: first, that stop transfer, like the initiation of translocation, is receptor-mediated; second, that at least some of the topology-determining events at the ER membrane can be regulated (an example is provided where regulation may occur developmentally [PrP] and a possible example where receptor interactions for stop transfer seem to have been dissociated from those of integration in the membrane, in the course of evolution [apo B]); third, that these variations on the universal mechanism of eukaryotic secretory and transmembrane protein biogenesis can occur either through the variations in sequences presented to the common machinery of translocation or through variations in the machinery with which these sequences interact. Thus, on the one hand, at least some of these variations are directed by signal and stop transfer sequence subtypes and, on the other hand, in at least one case, a special cytoplasmic factor distinct from the core machinery for chain translocation also seems to be involved (RRL cytosolic factor effect on PrP topology) in the special handling of the STE stop transfer sequence subtype. In another case, the conserved universal machinery is engaged by a protein (apo B) to carry out an unusual, if not unique, mechanism presumably related to the lipid carrying role of this soluble secretory protein. Whether stop transfer sequence subtypes are involved here remains to be demonstrated, but it is a tempting hypothesis. Taken together, these findings suggest that the ER is more than a barrier to be overcome in protein export. In some cases, it plays a regulatory role in gene expression (e.g., alternate fates of PrP), and in other cases, it plays a role as a specialized assembly line for biogenesis of proteins with unusual properties. It seems likely that many other examples of proteins using these two mechanisms will be found, as well as entirely different variations on the mechanisms of protein biogenesis. A common conceptual theme is likely to be that they are all directed by discrete sequences within the particular newly synthesized proteins engaging both/either the common and/or distinctive component of the cellular machinery for protein biogenesis.