Pushing the signal hypothesis: what are the limits?

Recent advances in understanding the in vitro translocation of nascent polypeptides across the endoplasmic reticulum (ER) membrane have established a molecular basis for the initial reactions predicted by the signal hypothesis. The first two events involve a transient arrest of nascent chain elongation, followed by a docking maneuver with the ER membrane which releases this block. It is not clear, however, that such signal sequence-mediated transfer occurs in the case of all proteins, or for that matter in all cell-free translation systems.