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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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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. |
format | Online Article Text |
id | pubmed-5567652 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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