Protein secretion signal hypothesis

Fig. 1. The process of protein secretion according to the signal hypothesis.

The signal hypothesis postulates the existence of several proteins necessary for secretion. These include the components of the SRP, which is proposed to bind to the signal sequence and block further translation of the mRNA coding for the mature protein SRP receptor, or docking protein, which relieves the translation block imposed by the SRP ribophorins, which bind the ribosome to the ER membrane signal peptidase and signal-peptide peptidase, discussed above and other proteins, which form a pore or transport apparatus in the membrane. Some of these proteins, the SRP, SRP receptor, signal peptidase, and ribophorins, have been isolated from eukaryotic cell extracts and characterized. 

Wickner (1980) proposed an alternative mechanism of protein secretion, called the membrane trigger hypothesis. This model proposes that the signal sequence influences the precursor protein or a domain of the precursor to fold into a conformation that can spontaneously partition into the hydrophobic part of the bilayer. In prokaryotes, the membrane potential causes the protein to traverse the bilayer. The protein then regains a water-soluble conformation, and is expelled into the medium. Signal peptidase removes the signal sequence during or after this process. Thus, secretory proteins or domains are transported across the membrane posttranslationally without the aid of a proteinaceous secretory apparatus. An energy source, such as the membrane potential, is required for secretion. 

In eukaryotic systems, secretion of a protein across the ER requires the presence of a functional signal sequence and participation of SRP, the membrane and associated as yet undefined export apparatus, the SRP receptor, and a signal peptidase. Biochemical evidence derived from experiments in in vitro translocation systems generally supports the signal hypothesis (see Section II,C). 

These observations are strong evidence in favour of the signal hypothesis of Blobel and Dobberstein, who proposed that secreted proteins are produced with an extra A/-terminal sequence that facilitates the passage of the nascent polypeptide through the cjrtoplasmic membrane. The N-term-... 

Signal hypothesis for the transmembrane transfer of secreted or membrane proteins, appears as a rather general process occurring in prokaryotes as well as in eukaryotes. Furthermore it does not seem specific for proteins synthesized by RER-bound polysomes and has also been described for proteins synthesized by free polysomes especially peroxisomal (Goldman and Blobel, 1978) and mitochondrial proteins (Maccechini et aU 1979, Cote et a/., 1979). 

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