Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 11, Pages 3447-3455Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.012526
Keywords
pancreas; protease; protease inhibitor; trypsin; trypsinogen; chymotrypsin C; mesotrypsin
Categories
Funding
- National Institutes of Health [R01 DK058088]
- National Research, Development and Innovation Office of Hungary [PD120960, FK127942]
- European Union
- European Social Fund
- University of Debrecen OTKA Bridge Fund
- Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00514/19/5]
- [EFOP-3.6.3-VEKOP-16-2017-00009]
Ask authors/readers for more resources
Mesotrypsin is an unusual human trypsin isoform with inhibitor resistance and the ability to degrade trypsin inhibitors. Degradation of the protective serine protease inhibitor Kazal type 1 (SPINK1) by mesotrypsin in the pancreas may contribute to the pathogenesis of pancreatitis. Here we tested the hypothesis that the regulatory digestive protease chymotrypsin C (CTRC) mitigates the harmful effects of mesotrypsin by cleaving the autolysis loop. As human trypsins are post-translationally sulfated in the autolysis loop, we also assessed the effect of this modification. We found that mesotrypsin cleaved in the autolysis loop by CTRC exhibited catalytic impairment on short peptides due to a 10-fold increase in K-m, it digested ?-casein poorly and bound soybean trypsin inhibitor with 10-fold decreased affinity. Importantly, CTRC-cleaved mesotrypsin degraded SPINK1 with markedly reduced efficiency. Sulfation increased mesotrypsin activity but accelerated CTRC-mediated cleavage of the autolysis loop and did not protect against the detrimental effect of CTRC cleavage. The observations indicate that CTRC-mediated cleavage of the autolysis loop in mesotrypsin decreases protease activity and thereby protects the pancreas against unwanted SPINK1 degradation. The findings expand the role of CTRC as a key defense mechanism against pancreatitis through regulation of intrapancreatic trypsin activity.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available