Proteomics/Proteolytic processing/Proteolytic processing in Secretory Pathway

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Proteolytic processing in Secretory Pathway[edit]

Proteolysis of Precursor proteins regulates many cellular processes like gene expression, embryogenesis, cell cycle, programmed cell death, intracellular protein targeting and endocrine/neural functions. All these processes needs proteolytic cleavage of the precursor protein and in this context this can be done by serine proteases in the secretory pathway. These proteases are calcium dependent serine endoproteases and are related to yeast and subtilisin proteases and therefore called Subtilisin-like Proprotein Convertases (SPCs) or PCs. Till now they identified & characterized seven members of this family in mammals and they have conserved signal peptides, pro-regions, catalytic and P-domains but they differ in C-terminal domains. These proteases get activated by autocatalytic cleavage of an N-terminal propeptide just like Subtilisin which is required for folding and activity. Studies predict that an eight-stranded beta barrel is formed due to folding of the P domain which interacts through a hydrophobic patch to a catalytic domain. Folding and activity requires a downstream domain of 150 amino acids named P- or Homo B-domain which plays a regulatory role, influencing both the calcium dependence and pH optima. Here the C-terminal regions play a minor in subcellular routing. Furin, one of the seven members of the SPCs, serves as a model for other PCs. The autoactivation mechanism involves intramolecular cleavage of prodomain that allows furin to exit the endoplasmic reticulum (ER). Until the cleaved inactive proenzyme reaches the trans Golgi Network (TGN) where dissociation of prodomain is facilitated by calcium-enriched environment and acidic pH conditions, the prodomain remains attached noncovalently to it. For full activation, further inhibitory reactions takes place within the prodomain by a second cleavage. Proinsulin, Proglucagon and POMC are the well studied peptide hormone precursors. PCs are responsible for the cleavage at specific sites in each of these precursors. The most frequent sites for cleavage are KR and RR. Proglucagon is processed by PC2 in the alpha cells and by PC1/PC3 in the intestinal L cells and releases active forms of glucagons-like peptides namely GLP-1 and GLP-2. The convertases PC2 and PC1/PC3 are majorly expressed in brain and neuroendocrine system to act on neuropeptide precursors in the secretory pathway. Glucose, the second messengers in the neuroendocrine cells regulates the transcription and translation of PC2 and PC1/PC3. Other convertases like PC4 expressed in testis and an isoform of PC6 that lacks a TM domain belong to PC family. Recently discovered convertases are PC7, furin, PACE4 and PC6B. These are expressed in tissues like liver, gut, brain, neuroendocrine system. There are still many unidentified enzymes that participate in cleavages at single basic residues and unusual sites, other than the sutilisin-like Proprotein Convertases.

Next section: Proteomics/Proteolytic processing/Examples of proteolytic processing in various organs of our body