BiP seals the pore.

Imagine inserting a piece of string into an inflated balloon without letting any of the air out. Ananalogous problem confronts cells in the production of integral membrane-spanning proteins, which must be inserted partway into the ER without letting the ER calcium stores leak into the cytoplasm. On page 261, Haigh and Johnson show that the ER lumenal chaperone protein BiP controls one end of a double door system at the translocon, the pore through which nascent proteins enter the ER, and propose a model to explain how the cell accomplishes the daunting task of regulating this double door.

On the cytoplasmic side of the ER membrane, the ribosome binds to the translocon to seal it while translocating a nascent polypeptide into the ER lumen. But the ribosome must break this seal to allow a cytoplasmic domain to extend into the cytoplasm. Some mechanism must exist to seal the lumenal side of the translocon when this happens.

Using a clever fluorescence quenching assay in isolated microsomes, the authors found that BiP is required to seal the lumenal side of the translocon pore at certain stages during the integration of a transmembrane protein, and that BiP can do this even in the absence of other lumenal proteins. This activity of BiP requires ATP hydrolysis, suggesting that the protein may use similar mechanisms in its diverse duties as a chaperone and pore sealer.

The authors propose that translation of a transmembrane sequence causes a BiP-mediated closure of the lumenal side of a translocon, allowing the ribosomal seal to be opened on the cytoplasmic side without breaching the ER membrane. Future studies will focus on identifying the domains of BiP responsible for sealing the translocon, and determining how BiP and the ribosome coordinate their actions across the ER membrane. ▪