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Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia
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-try...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780998/ https://www.ncbi.nlm.nih.gov/pubmed/31337736 http://dx.doi.org/10.1084/jem.20190701 |
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author | Le, Quang T. Lyons, Jonathan J. Naranjo, Andrea N. Olivera, Ana Lazarus, Robert A. Metcalfe, Dean D. Milner, Joshua D. Schwartz, Lawrence B. |
author_facet | Le, Quang T. Lyons, Jonathan J. Naranjo, Andrea N. Olivera, Ana Lazarus, Robert A. Metcalfe, Dean D. Milner, Joshua D. Schwartz, Lawrence B. |
author_sort | Le, Quang T. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6780998 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-67809982020-04-07 Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia Le, Quang T. Lyons, Jonathan J. Naranjo, Andrea N. Olivera, Ana Lazarus, Robert A. Metcalfe, Dean D. Milner, Joshua D. Schwartz, Lawrence B. J Exp Med Research Articles 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. Rockefeller University Press 2019-10-07 2019-07-23 /pmc/articles/PMC6780998/ /pubmed/31337736 http://dx.doi.org/10.1084/jem.20190701 Text en © 2019 Le et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Le, Quang T. Lyons, Jonathan J. Naranjo, Andrea N. Olivera, Ana Lazarus, Robert A. Metcalfe, Dean D. Milner, Joshua D. Schwartz, Lawrence B. Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
title | Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
title_full | Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
title_fullStr | Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
title_full_unstemmed | Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
title_short | Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
title_sort | impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780998/ https://www.ncbi.nlm.nih.gov/pubmed/31337736 http://dx.doi.org/10.1084/jem.20190701 |
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