Fig. 1. Potential sites of error during co-translational insertion of membrane proteins at the ER.

Membrane protein biogenesis at the ER begins with targeting of a translating nascent chain to an hour-glass shaped channel called the Sec61 translocon. The nascent chain is inserted into the Sec61 translocon and then partitions into the phospholipid bilayer through a lateral gate. During this process there are several instances where errors may arise. (A) Orientation of the first TMD as it enters the membrane, where the N-terminus must be correctly localised to the ER lumen (N_exo) or cytoplasm (N_cyt). This orientation defines the topology of the subsequent TMDs, meaning errors at this stage can result in incorrect topology of the entire protein. (B) Failed insertion of poor TMDs. Some TMDs are weakly hydrophobic or charged and, as a result, may not insert correctly in the absence of their cognate binding TMDs. (C) Misfolding of soluble domains. In some instances, MPs contain large soluble domains, which are required to fold correctly for overall protein fold. Failure to fold such domains can therefore also impact TMD packing.