Endoplasmic Reticulum

ID #1270

Is it possible for a protein that spans the membrane of the ER multiple times to have it's signal peptide attached at the N-terminus therefore having its signal peptide chopped off? I always thought that a protein that had its signal peptide cleaved by signal peptidase can only have it's N-terminus inside the lumen of the ER, and that it can only be a single-pass transmembrane protein only...


The concept of where your N-terminus is going to end up is separate from the concept of how many times you span the membrane. So in your last sentence: "I always thought that a protein that had its signal peptide cleaved by signal peptidase can only have it's N-terminus inside the lumen of the ER, and that it can only be a single-pass transmembrane protein only", the first part is correct. If your first presented signal is an amino-terminal signal sequence, it will get chopped off. But the second half of your sentence is incorrect. If you have a stop transfer sequence after that, then a second signal sequence (this one internal), then another stop transfer sequence, for example, you'd span the membrane three times. Notice that multi-pass proteins don't all have to start with internal signal sequences; they can just as easily start with amino-terminal signal sequences, which changes where their N-terminus will end up.

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