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
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.
Available from: Joana Vitte
- "Frequencies of haplotypes of the two loci on chromosome 16 were 50% for ␤␤/␤␣, 29–25% ␤␤/␤␤ and 21–25% of ␤␣/␤␣ (Soto et al., 2002; Schwartz, 2006). Baseline tryptase levels are often used as a surrogate for an individual's mast cell burden, and therefore genetic variations may interfere with assumptions made on this basis (Soto et al., 2002; Trivedi et al., 2008, 2009). In particular, the diagnosis of mastocytosis may be more difficult in patients with less functional alleles, especially for alpha tryptase. "
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ABSTRACT: The most abundant prestored enzyme of human mast cell secretory granules is the serine-protease tryptase. In humans, there are four tryptase isoforms, but only two of them, namely the alpha and beta tryptases, are known as medically important. Low levels of continuous tryptase production as an immature monomer makes up the major part of the baseline serum tryptase levels, while transient release of mature tetrameric tryptase upon mast cell degranulation accounts for the anaphylactic rise of serum tryptase levels. Serum tryptase determination contributes to the diagnosis or monitoring of mast cell disorders including mast cell activation - induced anaphylaxis, mastocytosis and a number of myeloproliferative conditions with mast cell lineage involvement. Baseline serum tryptase levels are predictive of the severity risk in some allergic conditions.
Available from: uu.diva-portal.org
Available from: Bruce S Bochner
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ABSTRACT: This review summarizes selected articles appearing in 2008 in the Journal. Articles chosen include those improving our understanding of mechanisms of allergic diseases by focusing on human basophil, mast cell, and eosinophil biology; IgE and its high-affinity receptor on various cells; novel properties of omalizumab; airways remodeling; and genetics. Articles from other journals have been included to supplement the topics presented.
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