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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...

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Autores principales: Le, Quang T., Lyons, Jonathan J., Naranjo, Andrea N., Olivera, Ana, Lazarus, Robert A., Metcalfe, Dean D., Milner, Joshua D., Schwartz, Lawrence B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
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.
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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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