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Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity
- Source :
- PLoS ONE, Vol 12, Iss 8, p e0183507 (2017), PLoS ONE
- Publication Year :
- 2017
- Publisher :
- Public Library of Science (PLoS), 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Physiology
medicine.medical_treatment
Cell Membranes
lcsh:Medicine
Molting
Biochemistry
Epithelium
Animal Cells
Medicine and Health Sciences
lcsh:Science
Enzyme Precursors
Multidisciplinary
biology
medicine.diagnostic_test
Chemistry
Serine Endopeptidases
Antibodies, Monoclonal
Proteases
Transmembrane protein
Enzymes
Cell biology
Cellular Structures and Organelles
Cellular Types
Anatomy
Research Article
Proteolysis
03 medical and health sciences
Enzyme activator
Protein Domains
Zymogens
Cell Line, Tumor
Genetics
medicine
Point Mutation
Humans
Matriptase
Amino Acid Sequence
Serine protease
Protease
Sequence Homology, Amino Acid
030102 biochemistry & molecular biology
lcsh:R
Biology and Life Sciences
Proteins
Epithelial Cells
Cell Biology
CUB domain
Enzyme Activation
Biological Tissue
030104 developmental biology
Zymogen activation
Mutation
Enzymology
biology.protein
lcsh:Q
Serine Proteases
Physiological Processes
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....2c110184fe750149caa48b9f751031d7
- Full Text :
- https://doi.org/10.1371/journal.pone.0183507