Mutational Tail Loss Is an Evolutionary Mechanism for Liberating Marapsins and Other Type I Serine Proteases from Transmembrane Anchors

Human and mouse marapsins (Prss27) are serine proteases preferentially expressed by stratified squamous epithelia. However, mouse marapsin contains a transmembrane anchor absent from the human enzyme. To gain insights into physical forms, activities, inhibition, and roles in epithelial differentiati...

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Published in:	The Journal of biological chemistry 2013-04, Vol.288 (15), p.10588-10598
Main Authors:	Raman, Kavita, Trivedi, Neil N., Raymond, Wilfred W., Ganesan, Rajkumar, Kirchhofer, Daniel, Verghese, George M., Craik, Charles S., Schneider, Eric L., Nimishakavi, Shilpa, Caughey, George H.
Format:	Article
Language:	eng
Subjects:	Animals Cattle CHO Cells Cricetinae Cricetulus Enzymology Evolution Evolution, Molecular Guinea Pigs Humans Marapsin Membrane Membrane Proteins - antagonists & inhibitors Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Mutant Strains Mole Rats Molecular Evolution Mutation Pan paniscus Pan troglodytes Prosemin Prostasin Protease Protease Inhibitors - pharmacology Prss27 Rats Serine Endopeptidases - genetics Serine Endopeptidases - metabolism Serine Protease Solubility Species Specificity Tryptase
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Summary:	Human and mouse marapsins (Prss27) are serine proteases preferentially expressed by stratified squamous epithelia. However, mouse marapsin contains a transmembrane anchor absent from the human enzyme. To gain insights into physical forms, activities, inhibition, and roles in epithelial differentiation, we traced tail loss in human marapsin to a nonsense mutation in an ancestral ape, compared substrate preferences of mouse and human marapsins with those of the epithelial peptidase prostasin, designed a selective substrate and inhibitor, and generated Prss27-null mice. Phylogenetic analysis predicts that most marapsins are transmembrane proteins. However, nonsense mutations caused membrane anchor loss in three clades: human/bonobo/chimpanzee, guinea pig/degu/tuco-tuco/mole rat, and cattle/yak. Most marapsin-related proteases, including prostasins, are type I transmembrane proteins, but the closest relatives (prosemins) are not. Soluble mouse and human marapsins are tryptic with subsite preferences distinct from those of prostasin, lack general proteinase activity, and unlike prostasins resist antiproteases, including leupeptin, aprotinin, serpins, and α2-macroglobulin, suggesting the presence of non-canonical active sites. Prss27-null mice develop normally in barrier conditions and are fertile without overt epithelial defects, indicating that marapsin does not play critical, non-redundant roles in development, reproduction, or epithelial differentiation. In conclusion, marapsins are conserved, inhibitor-resistant, tryptic peptidases. Although marapsins are type I transmembrane proteins in their typical form, they mutated independently into anchorless forms in several mammalian clades, including one involving humans. Similar pathways appear to have been traversed by prosemins and tryptases, suggesting that mutational tail loss is an important means of evolving new functions of tryptic serine proteases from transmembrane ancestors. Background: Vertebrate marapsins can be either type I transmembrane proteases or unanchored. Results: Point mutations liberated marapsins from transmembrane peptides independently in human-related primates and other mammalian clades. Soluble marapsins are active and inhibitor-resistant. Conclusion: Mutational tail loss transformed transmembrane marapsins and related proteins into soluble proteases. Significance: These findings suggest a general evolutionary mechanism for evolving proteases with new properties and functions.
ISSN:	0021-9258 1083-351X