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The monogenic disorder called hereditary \u03b1-tryptasemia, due to increased \u03b1-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2\u03b1- and 2\u03b2-tryptase protomers (\u03b1\/\u03b2-tryptase) form naturally in individuals who express \u03b1-tryptase. \u03b1\/\u03b2-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 \u03b1\/\u03b2-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the \u03b1 subunit of the EGF-like module\u2013containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of \u03b1-tryptase protomers on neighboring \u03b2-tryptase protomers likely result in the novel substrate repertoire of \u03b1\/\u03b2-tryptase tetramers that in turn cause some of the clinical features of hereditary \u03b1-tryptasemia and of other disorders involving mast cells.<\/jats:p>","DOI":"10.1084\/jem.20190701","type":"journal-article","created":{"date-parts":[[2019,7,23]],"date-time":"2019-07-23T18:59:02Z","timestamp":1563908342000},"page":"2348-2361","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":125,"title":["Impact of naturally forming human \u03b1\/\u03b2-tryptase heterotetramers in the pathogenesis of hereditary \u03b1-tryptasemia"],"prefix":"10.1084","volume":"216","author":[{"given":"Quang T.","family":"Le","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2346-8189","authenticated-orcid":true,"given":"Jonathan J.","family":"Lyons","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea N.","family":"Naranjo","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Olivera","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Lazarus","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean D.","family":"Metcalfe","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3913-3869","authenticated-orcid":true,"given":"Joshua D.","family":"Milner","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-6729","authenticated-orcid":true,"given":"Lawrence B.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,7,23]]},"reference":[{"key":"2023072609362349500_bib1","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1111\/cea.12259","article-title":"Alpha-tryptase gene variation is associated with levels of circulating IgE and lung function in asthma","volume":"44","author":"Abdelmotelb","year":"2014","journal-title":"Clin. 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