Chimerism, point mutation, and truncation dramatically transformed mast cell δ-tryptases during primate evolution

• Published in: Journal of allergy and clinical immunology Vol. 121; no. 5; pp. 1262 - 1268
• Main Authors: Trivedi, Neil N., Raymond, Wilfred W., Caughey, George H.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.05.2008; Elsevier
• Subjects: Allergy and Immunology; Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Chimerism; chimpanzee; comparative evolution; Fundamental and applied biological sciences. Psychology; Fundamental immunology; gorilla; Gorilla gorilla; Humans; Immunopathology; Lemur; Macaca; macaque; mast cells; Mast Cells - enzymology; Medical sciences; Models, Molecular; Molecular Sequence Data; orangutan; Pan troglodytes; Phylogeny; Point Mutation; Pongo pygmaeus; Primates - genetics; Protein Structure, Quaternary; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Tryptase; Tryptases - chemistry; Tryptases - genetics; gorilla; macaque; orangutan; Tryptase; chimpanzee; MCP; mast cells; comparative evolution; mMCP; Mouse mast cell protease; Mast cell protease; Transformed cell; Monkey; Cell transformation; Carcinogenesis; Truncation; Immunology; Primates; Evolution; Immunopathology; Serine endopeptidases; Enzyme; Peptidases; Vertebrata; Mammalia; Animal; Point mutation; Hydrolases; Mast cell; Chimerism; Comparative study
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2008.01.019

Tryptases are serine peptidases stored in mast cell granules. Rodents express 2 soluble tryptases, mast cell proteases (MCPs) 6 and 7. Human α- and β-tryptases are orthologs of MCP-6. However, much of the ancestral MCP-7 ortholog was replaced by parts of other tryptases, creating chimeric δ-tryptase. Human δ-tryptase's limited activity is hypothesized to be due to truncation and processing mutations. We sought to probe the origins and consequences of mutations in primate δ-tryptases. Prosimian (lemur), monkey (macaque), great ape (orangutan, gorilla, and chimpanzee), and human δ-tryptase genes were identified by means of data mining and genomic sequencing. Resulting genes were analyzed phylogenetically and structurally. The seminal conversion event generating the δ-tryptase chimera occurred early because all primates studied contain δ-tryptase genes. Truncation, resulting from a nonsense mutation of Trp206, occurred much later, after orangutans and other great apes last shared an ancestor. The Arg-3Gln propeptide mutation occurred most recently, being present in humans and chimpanzees but not in other primates. Surprisingly, the major active tryptase in monkeys is full-length δ-tryptase, not β-tryptase, which is the main active tryptase in human subjects. Models of macaque δ-tryptase reveal that the segment truncated in human subjects contains antiparallel β-strands coursing through the substrate-binding cleft, accounting for truncation's drastic effect on activity. Transformations in the ancestral MCP-7–like gene during primate evolution caused dramatic variations in function. Although δ-tryptases are nearly inactive in humans, they are active and dominant in monkeys.