Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 May;121(5):1262-8.
doi: 10.1016/j.jaci.2008.01.019. Epub 2008 Mar 5.

Chimerism, Point Mutation, and Truncation Dramatically Transformed Mast Cell Delta-Tryptases During Primate Evolution

Affiliations

Chimerism, Point Mutation, and Truncation Dramatically Transformed Mast Cell Delta-Tryptases During Primate Evolution

Neil N Trivedi et al. J Allergy Clin Immunol. .

Abstract

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.

Similar articles

See all similar articles

Cited by 10 articles

See all "Cited by" articles

Publication types

Feedback