The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia
Open accessAbstract
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.
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“Recent studies have shown that in individuals with HαT, these heterotetramers increase vascular permeability by cleaving and activating protease-activated receptor-2 (PAR2) on endothelial cells, resulting in increased vascular leakage (14, 15).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [14]
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“A recent description of a / b -tryptase heterotetrameric tryptases, which have expanded biologic functions relative to mature b -tryptases, may offer a possible mechanism explaining MCA in these individuals. 128,129”
From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [128]
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Metadata
- Authors
- Le, Q. T., Lyons, J. J., Naranjo, A. N., Olivera, A., Lazarus, R. A., Metcalfe, D. D., Milner, J. D., & Schwartz, L. B.
- Affiliations
- Virginia Commonwealth University (US)
- National Institutes of Health (US)
- Genentech (US)
- Corresponding author
- Schwartz, Lawrence B.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-07-23
- Volume
- 216
- Issue
- 10
- Pages
- 2348-2361
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6780998
- OpenAlex
- W2964163570
- Cited by
- 126
- References
- 54
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 13 · 2023: 18 · 2022: 17 · 2021: 24 · 2020: 16 · 2019: 8
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Charles Thomas Research Fund
- Medical College of Virginia Foundation
- National Institutes of Health (U18AI77435, R0127517)
- Division of Intramural Research of the National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hematology › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Keywords
- hereditary alpha-tryptasemia, beta-tryptase, heterotetramer, mast cells, protease-activated receptor 2, mast cell degranulation, autonomic dysfunction, allosteric effects, protease specificity, mast cell disease
- MeSH terms
- Adult, Allosteric Regulation, Female, Humans, Male, Mast Cells, Vibration, Cell Degranulation, Genetic Diseases, Inborn, Receptors, G-Protein-Coupled, Receptor, PAR-2, Tryptases, Protein Multimerization
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