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

Cardiovascular Research Institute of the University of California at San Francisco, San Francisco, CA, USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 06/2008; 121(5):1262-8. DOI: 10.1016/j.jaci.2008.01.019
Source: PubMed


Tryptases are serine peptidases stored in mast cell granules. Rodents express 2 soluble tryptases, mast cell proteases (MCPs) 6 and 7. Human alpha- and beta-tryptases are orthologs of MCP-6. However, much of the ancestral MCP-7 ortholog was replaced by parts of other tryptases, creating chimeric delta-tryptase. Human delta-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 delta-tryptases.
Prosimian (lemur), monkey (macaque), great ape (orangutan, gorilla, and chimpanzee), and human delta-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 delta-tryptase chimera occurred early because all primates studied contain delta-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 delta-tryptase, not beta-tryptase, which is the main active tryptase in human subjects. Models of macaque delta-tryptase reveal that the segment truncated in human subjects contains antiparallel beta-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 delta-tryptases are nearly inactive in humans, they are active and dominant in monkeys.

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