Secretory pathway, protein folding

Protein trafficking is the transport of proteins to their correct subcellular compartments or to the extracellular space ( secretory pathway ). Endo- and exocytosis describe vesicle budding and fusion at the plasma membrane and are by most authors not included in the term protein trafficking. Protein quality control comprize all cellular mechanisms, monitoring protein folding and detecting aberrant forms. 

Exit from the ER may be the rate-limiting step in the secretory pathway. In this context, it has been found that certain proteins play a role in the assembly or proper folding of other proteins without themselves being components of the latter. Such proteins are called molecular chaperones a number of important properties of these proteins are listed in Table 46—5, and the names of some of particular importance in the ER are listed in Table 46-6. Basically, they stabilize unfolded... 

Plant-based production systems are now being used commercially for the synthesis of foreign proteins [1-3]. Post-translational modification in plant cells is similar to that carried out by animal cells plant cells are also able to fold multimeric proteins correctly. The sites of glycosylation on plant-produced mammalian proteins are the same as on the native protein however, processing of N-linked glycans in the secretory pathway of plant cells results in a more diverse array of glycoforms than is produced in animal expression systems [4]. Glycoprotein activity is retained in plant-derived mammalian proteins. 

Trombetta, E. S. and Parodi, A. J. Quality control and protein folding in the secretory pathway. Annu. Rev Cell Dev Biol. 19 649-676, 2003. 

After translation, proteins destined for the secretory pathway (see p. 228) first have to fold into their native conformation within the rER (see p. 230). During this process they are supported by various auxiliary proteins. 

Recently a variety of modifiers of ubiquitin ligases have been discovered33 1 as have ubiquitin-like domains in other proteins. These findings elucidate the complexity of the sorting of proteins and removal of improperly folded and otherwise defective proteins from the secretory pathway and return to the proteasomes in the cytosol.dd ee They also suggest important roles for ubiquitination in a broad range of metabolic controls. 

At least two major slow processes occur in the folding of disulfide-containing proteins the cis-trans isomerizations of Xaa-Pro peptide bonds and the formation of the correct disulfide bonds. The latter is catalyzed by protein disulfide-isomerase (PDl). This enzyme occurs at high concentration in the endoplasmic reticulum (Hawkins et al., 1991) and there is good experimental evidence that PDl is required for the de novo folding of nascent secretory proteins (Bulleid and Freedman, 1988). Cyclophilins have recently also been localized in the ER (Hasel et al., 1991) and in other compartments of the secretory pathway (Caroni et al., 1991). Their biological function is not known. 

Schrag, J.D., Procopio, D.O., Cygler, M., Thomas, D.Y. and Bergeron, J.J. (2003) Lectin control of protein folding and sorting in the secretory pathway. Trends Biochem. Sci. 28, 49-57. 

Tatzelt J, Winklhofer KF (2004) Folding and misfolding of the prion protein in the secretory pathway. Amyloid 11 162-172... 

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