impact of naturally forming human tryptase heterotetramers in the pathogenesis of hereditary tryptasemia both tryptase and tryptase are preferentially expressed by human mast cells but the purpose of tryptase is enigmatic because its tetramers lack protease activity whereas tryptase tetramers are active proteases the monogenic disorder called hereditary tryptasemia due to increased tryptase gene copies and protein expression presents with clinical features such as vibratory urticaria and dysautonomia we show that heterotetramers composed of 2 and 2tryptase protomers tryptase form naturally in individuals who express tryptase tryptase but not homotetramer activates proteaseactivated receptor2 par2 which is expressed on cell types such as smooth muscle neurons and endothelium also only tryptase makes mast cells susceptible to vibrationtriggered degranulation by cleaving the subunit of the egflike modulecontaining mucinlike hormone receptorlike 2 emr2 mechanosensory receptor allosteric effects of tryptase protomers on neighboring tryptase protomers likely result in the novel substrate repertoire of tryptase tetramers that in turn cause some of the clinical features of hereditary tryptasemia and of other disorders involving mast cells