Progastriscin: Structure, Function, and Its Role in Tumor Progression

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Journal of Molecular Cell Biology (Impact Factor: 6.77). 03/2010; 2(3):118-27. DOI: 10.1093/jmcb/mjq001
Source: PubMed


Progastricsin (PGC) is a major seminal plasma protein having aspartyl proteinases-like activity and showing close sequence similarity to pepsins. PGC is also present as zymogen in gastric mucosa. In this article, we have reviewed all important features of PGC. Furthermore, we have compared all features of PGC with those of different aspartyl proteinases. The complete amino acid sequence of PGC reveals that it is composed of 374 residues (gastricsin moiety of 331 residues and the activation segment of 43 residues). The gene of human PGC is located at single locus on chromosome 6, whereas the human pepsinogen genetic locus is polymorphic and codes for at least three distinct polypeptide sequences on chromosome 11. The major useful function of PGC includes production of pro-antimicrobial substance in seminal plasma. The crystal structure of human PGC is known, which shows that it is quite similar to that of porcine pepsinogen. The tertiary structure of PGC is comprised of commonly bilobal structure with a large active-site cleft between the lobes. Two aspartate residues in the center of the cleft, namely Asp32 and Asp215, function as catalytic residues. The sequence and structural features of PGC indicate that it is diverged from its pepsinogen ancestor in the early phase of the evolution of gastric aspartyl proteinases. Our detailed review of PGC structure, function and activation mechanism will also be of interest to cancer biologists as well as gastroenterologists.

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    • "The main objective behind homology modeling is to ensure overall quality of the models, accuracy of prediction and evaluating the parameters provided by the various tools. Homology modeling is widely used in structure-based drug discovery [13] [14] [15] [16] [17] [18] [19]. Homology modeling can be employed to study the effect of mutations on the protein structure, active site prediction, designing novel drugs, and to study folding patterns using molecular dynamics (MD) simulations [20] [21] [22]. "
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    • "There are two major cleavage sites in human PGC, one located between pPhe26 and pLeu27 and the second located at the last residue of the prosegment pLeu43 and the first residue of the enzyme moiety Ser1 [1], [3], [25]. In a neutral pH the prosegment is coupled to the enzyme moiety by electrostatic interactions and hydrogen-bonds, pLys37, pTyr38 and Tyr9 (Fig. 1 green boxes) bind to the catalytic aspartates (Fig. 1 black boxes “+”) [1], [26], [27], [28] In an acidic pH environment acidic residues in the enzyme moiety become protonated disrupting electrostatic interactions with the prosegment (which has a basic character), releasing the prosegment for proteolytic cleavage and enzyme activation [3], [29], [30]. In fish pepsinogens a deletion of several residues in the prosegment is observed (Fig. 1 activation segment, lower black bar) leads to a decrease in the number of basic residues in the prosegment, and given the PI values for each enzyme region (Table 1), we deduced that the activation of fish pepsinogens occurs in conditions that are comparatively more alkaline. "
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    ABSTRACT: Aspartic proteases comprise a large group of enzymes involved in peptide proteolysis. This collection includes prominent enzymes globally categorized as pepsins, which are derived from pepsinogen precursors. Pepsins are involved in gastric digestion, a hallmark of vertebrate physiology. An important member among the pepsinogens is pepsinogen C (Pgc). A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga). Although gene sequences with similarity to Pgc have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far. By combining phylogenetics and genomic analysis, we find an unexpected Pgc diversity in the vertebrate sub-phylum. We were able to reconstruct gene duplication timings relative to the divergence of major vertebrate clades. Before tetrapod divergence, a single Pgc gene tandemly expanded to produce two gene lineages (Pgbc and Pgc2). These have been differentially retained in various classes. Accordingly, we find Pgc2 in sauropsids, amphibians and marsupials, but not in eutherian mammals. Pgbc was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to Pgb and Pgc1. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. Pgb was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of Pgc2 and Pgbc have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation. We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats.
    PLoS ONE 03/2012; 7(3):e32852. DOI:10.1371/journal.pone.0032852 · 3.23 Impact Factor
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    Fisheries Science 09/2010; 76(5):819-826. DOI:10.1007/s12562-010-0275-x · 0.88 Impact Factor
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