Synthesis at the rough endoplasmic reticulum (RER) determines the orientation of integral membrane proteins in plasma membranes. Though like the process for secreted proteins, there are some twists:

1. The signal sequence, doubling as a hydrophobic anchor, isn't at the amino end; it's internal.

2. Charges around the sequence cause it to enter the translocation pore amino end out.

3. The signal, hidden in the pore, isn't cleaved.

     Translation finished normally, with the remainder of the protein passing through the translocation pore - but the embedded amino end is left dangling in the cytosol. When transported to the plasma membrane, the protein's amino end is incorporated, still facing the cytosol.