Abstract
Casein phosphopeptides (CPPs) containing chelated calcium drastically increase the secretion of extracellular homologous and heterologous proteins in filamentous fungi. Casein phosphopeptides released by digestion of alpha − and beta-casein are rich in phosphoserine residues (SerP). They stimulate enzyme secretion in the gastrointestinal tract and enhance the immune response in mammals, and are used as food supplements. It is well known that casein phosphopeptides transport Ca2+ across the membranes and play an important role in Ca2+ homeostasis in the cells. Addition of CPPs drastically increases the production of heterologous proteins in Aspergillus as host for industrial enzyme production. Recent proteomics studies showed that CPPs alter drastically the vesicle-mediated secretory pathway in filamentous fungi, apparently because they change the calcium concentration in organelles that act as calcium reservoirs. In the organelles calcium homeostasis a major role is played by the pmr1 gene, that encodes a Ca2+/Mn2+ transport ATPase, localized in the Golgi complex; this transporter controls the balance between intra-Golgi and cytoplasmic Ca2+ concentrations. A Golgi-located casein kinase (CkiA) governs the ER to Golgi directionality of the movement of secretory proteins by interacting with the COPII coat of secretory vesicles when they reach the Golgi. Mutants defective in the casein-2 kinase CkiA show abnormal targeting of some secretory proteins, including cytoplasmic membrane amino acid transporters that in ckiA mutants are miss-targeted to vacuolar membranes. Interestingly, addition of CPPs increases a glyceraldehyde-3-phpshate dehydrogenase protein that is known to associate with microtubules and act as a vesicle/membrane fusogenic agent. In summary, CPPs alter the protein secretory pathway in fungi adapting it to a deregulated protein traffic through the organelles and vesicles what results in a drastic increase in secretion of heterologous and also of some homologous proteins.
Highlights
What are casein phosphopeptides? Role in calcium transport in the intestinal tract Casein phosphopeptides (CPPs) are bioactive peptides derived from casein which are rich in phosphoserine
CPPs are present in milk from all studied mammalians but usually we refer to those obtained from bovine casein
The endogenous yeast invertase, a glycosylated enzyme is more efficiently secreted in the PMR1 mutants, the secreted invertase lacks the branched mannose outer residues that are added during passage through the Golgi. These results suggest that alteration of the PMR1-encoded Ca2+ ionpump results in incompletely glycosylated proteins and more efficient packaging and secretion of these incompletely glycosylated forms
Summary
What are casein phosphopeptides? Role in calcium transport in the intestinal tract Casein phosphopeptides (CPPs) are bioactive peptides derived from casein which are rich in phosphoserine. Proteomics studies using cultures of A. awamori showed that supplementation with CPPs resulted in a drastic increase in the secretion of cell-wall synthesizing enzymes and several other extracellular enzymes which are known to be secreted through the vesicle-mediated secretory pathway [38]. From Golgi to the cell membrane and the extracellular medium Filamentous fungi grow by apical extension at a relatively high speed (up to 0.5 μm per min) [92] This implies that cell-wall precursors, cell wall synthesizing enzymes and other secretory proteins have to move relatively long distances in the hyphae [93] since it is well known that secretion of those enzymes concentrates at the apical and subapical regions [94,95,96,97]. Addition of casein phosphopeptides has a dramatic effect on secretion of homologous, and of heterologous proteins, in filamentous fungi This evidence is reinforced by recent studies on proteomics of unsupplemented and CPPs-supplemented fungal cells. Competing interests The author declare that he has no competing interests
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