Pathways secretory

CH2SH + 1/2 O2 -CH2-S-S-CH2 + H2O This reaction requires an oxidative environment, and such disulfide bridges are usually not found in intracellular proteins, which spend their lifetime in an essentially reductive environment. Disulfide bridges do, however, occur quite frequently among extracellular proteins that are secreted from cells, and in eucaryotes, formation of these bridges occurs within the lumen of the endoplasmic reticulum, the first compartment of the secretory pathway. 

A system of membrane enclosed cisternae in the cytoplasm. The ER is continuous with the outer membrane of the nuclear envelope. The part of the ER coated with ribosomes is called rough ER, the other part is called smooth-surfaced ER. The rough ER is the first compartment of the secretory pathway. Here, membrane proteins are integrated into and secretory proteins translocated across the ER membrane. Furthermore,... 

The synthesis of virtually all proteins in a cell begins on ribosomes in the cytosol (except a few mitochondrial, and in the case of plants, a few chloroplast proteins that are synthesized on ribosomes inside these organelles). The fate of a protein molecule depends on its amino acid sequence, which can contain sorting signals that direct it to its corresponding organelle. Whereas proteins of mitochondria, peroxisomes, chloroplasts and of the interior of the nucleus are delivered directly from the cytosol, all other organelles receive their set of proteins indirectly via the ER. These proteins enter the so-called secretory pathway (Fig. 1). 

Harter C, Reinhard C (2000) The secretory pathway from history to the state ofthe art. Subcell Biochem 34 1-38... 

GPI-anchored proteins constitute a quite diverse family of cell-surface molecules that participate in such processes as nutrient uptake, cell adhesion, and membrane signaling events [3]. All GPI-linked proteins are destined for the cell surface via trafficking through the secretory pathway, where they acquire the... 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

CNTF is expressed in glial cells within the central and peripheral nervous system. CNTF lacks a signal sequence and is not secreted by the classical secretory pathway, but is thought to convey its cytoprotective effects after release from adult glial cells by some mechanism induced by injury [3,5]. 

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. 

Once the proteins have passed the quality control system of the early secretory pathway, they are transported in vesicles via the individual compartments of the Golgi apparatus to the plasma membrane. Soluble proteins are transported in the vesicle lumen, membrane proteins are integrated in the vesicle membrane. The transport to the cell surface is the default pathway for secretory and membrane proteins. Proteins may also become part of one of the intracellular compartments along the secretory pathway, but only if they contain specific retention signals. 

Many diseases are known to be caused by the intracellular retention of mutant proteins or by the impairment of components of the secretory pathway [4]. The disease-causing mechanisms include ... 

Transport of proteins and lipids occurs between the organelles of the secretory pathway, i.e. endoplasmic reticulum (ER), Golgi, endosomes, lysosomes and the plasma membrane. 

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... 

Albumin (69 kDa) is the major protein of human plasma (3.4-4.7 g/dL) and makes up approximately 60% of the total plasma protein. About 40% of albumin is present in the plasma, and the other 60% is present in the extracellular space. The liver produces about 12 g of albumin per day, representing about 25% of total hepatic protein synthesis and half its secreted protein. Albumin is initially synthesized as a preproprotein. Its signal peptide is removed as it passes into the cisternae of the rough endoplasmic reticulum, and a hexapeptide at the resulting amino terminal is subsequently cleaved off farther along the secretory pathway. The synthesis of albumin is depressed in a variety of diseases, particularly those of the liver. The plasma of patients with liver disease often shows a decrease in the ratio of albumin to globulins (decreased albumin-globuhn ratio). The synthesis of albumin decreases rela-... 

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

Colley, N., Baker, E., Stamnes, M. and Zuker, C. (1991) The cyclophilin homolog ninaA is required in the secretory pathway. Cell 67, 255-263. 

Davis, E.C., Broekelmann, T.J., Ozawa, Y. and Mecham, R.P. (1998) Identification of tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in the secretory pathway. Journal of Cell Biology 140, 295-303. 

Lodish, H. F., and Kong, N. (1993). The secretory pathway is normal in dithiothreitol-treated cells, but disulfide-bonded proteins are reduced and reversibly retained in the endoplasmic reticulum. J. Biol. Chem. 268, 20598-20605. 

Spasic, D., Raemaekers, T., Dillen, K., Declerck, I., Baert, V., Serneels, L., Fullckrug, J., and Annaert, W. (2007) Rerlp competes with APH-1 for binding to nicastrin and regulates-secretase complex assembly in the early secretory pathway. J. Cell Biol. 176, 629-640. 

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. 

Proteins produced in plant cells can remain within the cell or are secreted into the apoplast via the bulk transport (secretory) pathway. In whole plants, because levels of protein accumulated intracellularly, e. g. using the KDEL sequence to ensure retention in the endoplasmic reticulum, are often higher than when the product is secreted [58], foreign proteins are generally not directed for secretion. However, as protein purification from plant biomass is potentially much more difficult and expensive than protein recovery from culture medium, protein secretion is considered an advantage in tissue culture systems. For economic harvesting from the medium, the protein should be stable once secreted and should accumulate to high levels in the extracellular environment. 

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