History of the Signal Hypothesis

Abstract The signal hypothesis, which describes how secretory and membrane proteins are targeted to the endoplasmic reticulum, was proposed in 1971 by Günter Blobel and David Sabatini and demonstrated by Blobel and Bernhard Dobberstein in 1975. Subsequent research identified the key components of the membrane insertion and translocation machinery, including the signal recognition particle (SRP), the SRP receptor and the protein‐conducting channel. Ultimately, the signal hypothesis was shown to be true for not only eukaryotes but also prokaryotes. Most importantly, the concept of signal‐mediated targeting was expanded into a general hypothesis of cellular topogenesis that helps to explain how proteins are distributed to their correct locations within the cell following their synthesis in the cytoplasm. Key Concepts: Modern cell biology was developed in the post‐World War II period. Cell biological research in the 30 years after World War II was characterised by a multidisciplinary approach that combined electron microscopy, cell fractionation, biochemical analysis and radioactive pulse‐labelling of proteins. Formulation of the signal hypothesis was an outgrowth of protein synthesis and secretion research carried out at the Rockefeller University beginning in the late 1940s. The signal hypothesis was originally proposed by Günter Blobel and David Sabatini in 1971, and demonstrated by Blobel and colleagues in 1975. The signal hypothesis showed that cytoplasmically synthesised proteins targeted to the ER use a signal sequence to direct them to the ER membrane. A signal sequence is a short peptide that is part of the original translation product of proteins targeted to the ER, often at the N ‐terminus of the protein, and is frequently removed proteolytically after translocation of the nascent polypeptide through the ER membrane. The mechanism of protein translocation was established through the isolation and characterisation of SRP, the SRP‐receptor and the protein‐conducting channel. The signal hypothesis was found to be applicable to protein translocation in all eukaryotes and prokaryotes. Although the original signal hypothesis proposed translocation of proteins during the elongation of the polypeptide chain (cotranslational), translocation was found to also occur in some instances after protein synthesis was complete (post‐translational), primarily through studies of bacteria and yeast. The concept of signal‐mediated targeting of proteins was expanded into a generalised hypothesis of protein topogenesis by Günter Blobel in 1980.