The Protein Translocation Machinery of the Endoplasmic Reticulum: The Signal Hypothesis Ten Years Later

Abstract

In 1975, the signal hypothesis was proposed by Blobel and Dobberstein to explain the targeting and translocation of secretory proteins across the endoplasmic reticulum (ER) membrane. Ten years later, molecular components of the cellular machinery catalyzing these events have been isolated and characterized. Our current view of the function of the signal recognition particle (SRP) and the SRP receptor (or docking protein) in the translocation of secretory and lysosomal proteins across—as well as integration of integral membrane proteins into—the ER membrane is described. In brief, SRP is thought to recognize the signal peptide on the nascent proteins and to arrest their translation in the cytoplasmic space. Upon interaction of the elongation-arrested ribosome with the correct target membrane (the ER), and particularly after a direct interaction of the ribosome-bound SRP with the SRP receptor in the ER membrane, the elongation arrest is released. A functional ribosome-membrane junction is established, allowing the translocation of the nascent polypeptide across the membrane by an as yet poorly understood mechanism.