Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles
Milk alpha-, beta- and kappa-casein proteins assemble into casein micelles in breast epithelial cells. The glycomacropeptide (GMP) tails of kappa-casein that extend from the surface of the micelle are key to assembly and aggregation. Aggregation is triggered by stomach pepsin cleavage of GMP from pa...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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The Royal Society
2019-10-01
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| Series: | Royal Society Open Science |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/pdf/10.1098/rsos.190939 |
| _version_ | 1818246629293031424 |
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| author | Jean Manguy Denis C. Shields |
| author_facet | Jean Manguy Denis C. Shields |
| author_sort | Jean Manguy |
| collection | DOAJ |
| description | Milk alpha-, beta- and kappa-casein proteins assemble into casein micelles in breast epithelial cells. The glycomacropeptide (GMP) tails of kappa-casein that extend from the surface of the micelle are key to assembly and aggregation. Aggregation is triggered by stomach pepsin cleavage of GMP from para-kappa-casein (PKC). While one casein micelle model emphasizes the importance of hydrophobic interactions, another focuses on polar residues. We performed an evolutionary analysis of kappa-casein primary sequence and predicted features that potentially impact on protein interactions. We noted more rapid change in the earlier period (166 to 60 Ma). Pepsin and plasmin cleavage sites were avoided in the GMP, which may partly explain its amino acid composition. Short tandem repeats have led to modest expansions of PKC, and to large GMP expansions, suggesting the GMP is less length constrained. Amino acid compositional constraints were assessed across species. Polarity and hydrophobicity properties were insufficient to explain differences between PKC and GMP. Among polar residues, threonine dominates the GMP, compared to serine, probably reflecting its preference for O-glycosylation over phosphorylation. Glutamine, enriched in the bovine PQ-rich region, is not positionally conserved in other species. Among hydrophobic residues, isoleucine is clearly preferred over leucine in the GMP, and patches of hydrophobicity are not markedly positionally conserved. PKC tyrosine and charged residues showed stronger conservation of position, suggesting a role for pi-interactions, seen in other structurally dynamic protein membraneless assemblies. Independent acquisitions of cysteines are consistent with a trend of increasing stabilization of multimers by covalent disulphide bonds, over evolutionary time. In conclusion, kappa-casein compositional and positional constraints appear to be influenced by modification preferences, protease evasion and protein–protein interactions. |
| first_indexed | 2024-12-12T14:51:51Z |
| format | Article |
| id | doaj.art-6eb9528bbb4546f7967b2a906eebc474 |
| institution | Directory Open Access Journal |
| issn | 2054-5703 |
| language | English |
| last_indexed | 2024-12-12T14:51:51Z |
| publishDate | 2019-10-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Royal Society Open Science |
| spelling | doaj.art-6eb9528bbb4546f7967b2a906eebc4742022-12-22T00:20:59ZengThe Royal SocietyRoyal Society Open Science2054-57032019-10-0161010.1098/rsos.190939190939Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micellesJean ManguyDenis C. ShieldsMilk alpha-, beta- and kappa-casein proteins assemble into casein micelles in breast epithelial cells. The glycomacropeptide (GMP) tails of kappa-casein that extend from the surface of the micelle are key to assembly and aggregation. Aggregation is triggered by stomach pepsin cleavage of GMP from para-kappa-casein (PKC). While one casein micelle model emphasizes the importance of hydrophobic interactions, another focuses on polar residues. We performed an evolutionary analysis of kappa-casein primary sequence and predicted features that potentially impact on protein interactions. We noted more rapid change in the earlier period (166 to 60 Ma). Pepsin and plasmin cleavage sites were avoided in the GMP, which may partly explain its amino acid composition. Short tandem repeats have led to modest expansions of PKC, and to large GMP expansions, suggesting the GMP is less length constrained. Amino acid compositional constraints were assessed across species. Polarity and hydrophobicity properties were insufficient to explain differences between PKC and GMP. Among polar residues, threonine dominates the GMP, compared to serine, probably reflecting its preference for O-glycosylation over phosphorylation. Glutamine, enriched in the bovine PQ-rich region, is not positionally conserved in other species. Among hydrophobic residues, isoleucine is clearly preferred over leucine in the GMP, and patches of hydrophobicity are not markedly positionally conserved. PKC tyrosine and charged residues showed stronger conservation of position, suggesting a role for pi-interactions, seen in other structurally dynamic protein membraneless assemblies. Independent acquisitions of cysteines are consistent with a trend of increasing stabilization of multimers by covalent disulphide bonds, over evolutionary time. In conclusion, kappa-casein compositional and positional constraints appear to be influenced by modification preferences, protease evasion and protein–protein interactions.https://royalsocietypublishing.org/doi/pdf/10.1098/rsos.190939caseinevolutionprotein disordercasein micelle |
| spellingShingle | Jean Manguy Denis C. Shields Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles Royal Society Open Science casein evolution protein disorder casein micelle |
| title | Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles |
| title_full | Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles |
| title_fullStr | Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles |
| title_full_unstemmed | Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles |
| title_short | Implications of kappa-casein evolutionary diversity for the self-assembly and aggregation of casein micelles |
| title_sort | implications of kappa casein evolutionary diversity for the self assembly and aggregation of casein micelles |
| topic | casein evolution protein disorder casein micelle |
| url | https://royalsocietypublishing.org/doi/pdf/10.1098/rsos.190939 |
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