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Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active mat...

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Autores principales: Tseng, Chun-Che, Jia, Bailing, Barndt, Robert, Gu, Yayun, Chen, Chien-Yu, Tseng, I-Chu, Su, Sheng-Fang, Wang, Jehng-Kang, Johnson, Michael D., Lin, Chen-Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567652/
https://www.ncbi.nlm.nih.gov/pubmed/28829816
http://dx.doi.org/10.1371/journal.pone.0183507
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author Tseng, Chun-Che
Jia, Bailing
Barndt, Robert
Gu, Yayun
Chen, Chien-Yu
Tseng, I-Chu
Su, Sheng-Fang
Wang, Jehng-Kang
Johnson, Michael D.
Lin, Chen-Yong
author_facet Tseng, Chun-Che
Jia, Bailing
Barndt, Robert
Gu, Yayun
Chen, Chien-Yu
Tseng, I-Chu
Su, Sheng-Fang
Wang, Jehng-Kang
Johnson, Michael D.
Lin, Chen-Yong
author_sort Tseng, Chun-Che
collection PubMed
description The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active matriptase and increase accessibility to substrates. We show here that matriptase shedding occurs via a de novo proteolytic cleavage at sites located between the SEA domain and the CUB domain. Point or combined mutations at the four positively charged amino acid residues in the region following the SEA domain allowed Arg-186 to be identified as the primary cleavage site responsible for matriptase shedding. Kinetic studies further demonstrate that matriptase shedding is temporally coupled with matriptase zymogen activation. The onset of matriptase shedding lags one minute behind matriptase zymogen activation. Studies with active site triad Ser-805 point mutated matriptase, which no longer undergoes zymogen activation or shedding, further suggests that matriptase shedding depends on matriptase zymogen activation, and that matriptase proteolytic activity may be involved in its own shedding. Our studies uncover an autonomous mechanism coupling matriptase zymogen activation, proteolytic activity, and shedding such that a proportion of newly generated active matriptase escapes HAI-1-mediated rapid inhibition by shedding into the extracellular milieu.
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spelling pubmed-55676522017-09-09 Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity Tseng, Chun-Che Jia, Bailing Barndt, Robert Gu, Yayun Chen, Chien-Yu Tseng, I-Chu Su, Sheng-Fang Wang, Jehng-Kang Johnson, Michael D. Lin, Chen-Yong PLoS One Research Article The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active matriptase and increase accessibility to substrates. We show here that matriptase shedding occurs via a de novo proteolytic cleavage at sites located between the SEA domain and the CUB domain. Point or combined mutations at the four positively charged amino acid residues in the region following the SEA domain allowed Arg-186 to be identified as the primary cleavage site responsible for matriptase shedding. Kinetic studies further demonstrate that matriptase shedding is temporally coupled with matriptase zymogen activation. The onset of matriptase shedding lags one minute behind matriptase zymogen activation. Studies with active site triad Ser-805 point mutated matriptase, which no longer undergoes zymogen activation or shedding, further suggests that matriptase shedding depends on matriptase zymogen activation, and that matriptase proteolytic activity may be involved in its own shedding. Our studies uncover an autonomous mechanism coupling matriptase zymogen activation, proteolytic activity, and shedding such that a proportion of newly generated active matriptase escapes HAI-1-mediated rapid inhibition by shedding into the extracellular milieu. Public Library of Science 2017-08-22 /pmc/articles/PMC5567652/ /pubmed/28829816 http://dx.doi.org/10.1371/journal.pone.0183507 Text en © 2017 Tseng et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tseng, Chun-Che
Jia, Bailing
Barndt, Robert
Gu, Yayun
Chen, Chien-Yu
Tseng, I-Chu
Su, Sheng-Fang
Wang, Jehng-Kang
Johnson, Michael D.
Lin, Chen-Yong
Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
title Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
title_full Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
title_fullStr Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
title_full_unstemmed Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
title_short Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
title_sort matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567652/
https://www.ncbi.nlm.nih.gov/pubmed/28829816
http://dx.doi.org/10.1371/journal.pone.0183507
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