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Characterization of Human -Tryptases, Novel Members of the Chromosome 16p Mast Cell Tryptase and Prostasin Gene Families¹

Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, CA 94143

Previously, this laboratory identified clusters of -, ß-, and mast cell protease-7-like tryptase genes on human chromosome 16p13.3. The present work characterizes adjacent genes encoding novel serine proteases, termed -tryptases, and generates a refined map of the multitryptase locus. Each gene lies between an 1H Ca²⁺ channel gene (CACNA1H) and a ßII- or ßIII-tryptase gene and is 30 kb from polymorphic minisatellite MS205. The tryptase locus also contains at least four tryptase-like pseudogenes, including mastin, a gene expressed in dogs but not in humans. Genomic DNA blotting results suggest that I- and II-tryptases are alleles at the same site. ßII- and ßIII-tryptases appear to be alleles at a neighboring site, and II- and ßI-tryptases appear to be alleles at a third site. -Tryptases are transcribed in lung, intestine, and in several other tissues and in a mast cell line (HMC-1) that also expresses -tryptase protein. Immunohistochemical analysis suggests that -tryptase is expressed by airway mast cells. -Tryptase catalytic domains are 48% identical with those of known mast cell tryptases and possess mouse homologues. We predict that -tryptases are glycosylated oligomers with tryptic substrate specificity and a distinct mode of activation. A feature not found in described tryptases is a C-terminal hydrophobic domain, which may be a membrane anchor. Although the catalytic domains contain tryptase-like features, the hydrophobic segment and intron-exon organization are more closely related to another recently described protease, prostasin. In summary, this work describes -tryptases, which are novel members of chromosome 16p tryptase/prostasin gene families. Their unique features suggest possibly novel functions.

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