Chimerism, point mutation, and truncation dramatically transformed mast cell delta-tryptases during primate evolution.
BACKGROUND
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.


OBJECTIVE
We sought to probe the origins and consequences of mutations in primate delta-tryptases.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Trivedi
Neil N
NN
Cardiovascular Research Institute of the University of California at San Francisco, San Francisco, CA, USA.
Raymond
Wilfred W
WW
Caughey
George H
GH
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D046528:Chimerism; D006071:Gorilla gorilla; D006801:Humans; D007900:Lemur; D008251:Macaca; D008407:Mast Cells / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010802:Phylogeny; D017354:Point Mutation; D011148:Pongo pygmaeus; D011323:Primates / Q000235:genetics*; D020836:Protein Structure, Quaternary; D053802:Tryptases / Q000737:chemistry / Q000235:genetics*
D053802:Tryptases