Protein secretion models

Despite large amounts of evidence concerning the requirements of protein secretion, the molecular mechanism of the process is still unclear. Various models of the export mechanism have been proposed. No one hypothesis accounts for all of the data collected to date it may be that one mechanism is insufficient to explain the many types of export that occur. In this section, some current models of protein secretion are... 

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. 

Although l,25(OH)2D3 is a potent inhibitor of Thl-dominated EAE and IFN-y secretion is clearly inhibited in vitro, l,25-(OH)2 D3 failed to suppress Thl cells in vivo using a myelin basic protein induction model of EAE [106]. At the same time, whatsoever, no upregulation of IL-4 transcription was observed in animals protected from EAE through l,25(OH)2D3 [106]. This study speaks against both putative immunoregulatory mechanisms in l,25(OH)2D3 action, inhibition ofThl responses as well as induction of Th2 responses. The immunomodulatory effects of 1,25 (OH)2D3 can therefore not entirely be attributed to and explained by effects on the Thl /Th2 cytokine balance. However, the majority of reports consistently demonstrate that Thl Tcells are relatively more susceptible to l,25(OH)2D3 treatment. This may also explain the clinical efficacy of l,25(OH)2D3 predominantly in the treatment of Thl-mediated diseases as outlined below. 

Figure 27.30 A current model for protein secretion by prokaryotes. 

Alcoholism. Many investigations showed that alcoholism modulates the level of PTM-like phosphorylation [47], Alcohol consumption was shown to decrease the sialic acid conjugation to transferrin, an important carrier protein secreted from the liver to blood and other glycoproteins. This observation led to the development of a laboratory test for chronic alcohol use. Similar studies showed that direct production of alcohol metabolism (alpha-hydroxyethyl radicals, acetaldehyde and lipid peroxides) causes PTM that correlates with alcohol consumption in animal models and human subjects [48]. 

Recently, the E. coli SecB was coexpressed in a subtilis strain with a modified SecA protein. Specifically, the 32 C-terminal residues of SecA of B. subtilis were replaced by the corresponding amino acids of E. coli SecA to optimize the SecA-SecB interaction. This engineering of the protein secretion machinery resulted in the increased secretion of a mutant maltose-binding protein (MalEl 1) and the alkaline phosphatase PhoA of . coli, which were used as model heterologous proteins [63]. It should be noted here that early studies by Collier also provided evidence that the heterologous expression of E. coli SecB in B. subtilis could be beneficial for the secretion of particular proteins [64]. 

Figure 2. Kinetics modelling results (a) specific growth rate, (b) protein secretion rate. Full lines represent the true kinetics and dashed-lines the modelling results.

The "competition" model provided an explanation of the characteristics of secretion of those extracellular enzymes which are formed at the maximum rate after the end of exponential growth and which account for a significant part of the bacterium s total protein output. A mathematical model of exoprotein production in bacteria has been proposed, recently, which is consistent with the "competition" mechanism (Coleman and Fowler, 1984). It should be emphasized that the ideas implicit in such a mechanism may have been overlooked by those interested in only a single extracellular enzyme rather that the summation of all the individual extracellular proteins secreted by an organism. However, within its framework the opportunity for individual components to respond to other specific regulatory devices is not excluded. 

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