Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-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 α/β-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the α subunit of the EGF-like module–containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of α-tryptase protomers on neighboring β-tryptase protomers likely result in the novel substrate repertoire of α/β-tryptase tetramers that in turn cause some of the clinical features of hereditary α-tryptasemia and of other disorders involving mast cells.

人肥大细胞优先表达α-胰蛋白酶和β-胰蛋白酶，但是α-胰蛋白酶的目的是神秘的，因为其四聚体缺乏蛋白酶活性，而β-胰蛋白酶四聚体是活性蛋白酶。由于增加的α-胰蛋白酶基因拷贝和蛋白质表达，这种称为遗传性α-胰血病的单基因疾病表现出诸如振动性荨麻疹和自主神经失调等临床特征。我们显示由2α-和2β-胰蛋白酶前体（α/β-胰蛋白酶）组成的异四聚体在表达α-胰蛋白酶的个体中自然形成。α/β-类胰蛋白酶而非同型四聚体可激活蛋白酶激活的受体2（PAR2），该受体在诸如平滑肌，神经元和内皮等细胞类型上表达。还，只有α/β-类胰蛋白酶通过切割含有粘蛋白样激素受体样2（EMR2）机械感觉受体的EGF样模块的α亚基，使肥大细胞易于受到振动触发的脱粒。α-胰蛋白酶前体对邻近的β-胰蛋白酶前体的变构作用可能导致α/β-胰蛋白酶四聚体的新底物库，继而引起遗传性α-胰酶血症和其他涉及肥大细胞的疾病的某些临床特征。