Both á-tryptase and â-tryptase are preferentially expressed by human mast cells, but the purpose of á-tryptase is enigmatic, because its tetramers lack protease activity, whereas â-tryptase tetramers are active proteases. The monogenic disorder called hereditary á-tryptasemia, due to increased á-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2á- and 2â-tryptase protomers (á/â-tryptase) form naturally in individuals who express á-tryptase. á/â-Tryptase, but not homotetramer, activates protease-activated receptor-2 (PAR2), which is expressed on cell types such as smooth muscle, neurons, and endothelium. Also, only á/â-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the á subunit of the EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of á-tryptase protomers on neighboring â-tryptase protomers likely result in the novel substrate repertoire of á/â-tryptase tetramers that in turn cause some of the clinical features of hereditary á-tryptasemia and of other disorders involving mast cells.
Adult Allosteric Regulation