Open AccessStructural Basis of the Pancreatitis-Associated Autoproteolytic Failsafe Mechanism in Human Anionic Trypsin
Author(s) -
Felix Nagel,
Anne Susemihl,
Norman Geist,
Kevin Möhlis,
Gottfried J. Palm,
Michael Lammers,
Mihaela Delcea
Publication year - 2022
Publication title -
journal of inflammation research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.656
H-Index - 33
ISSN - 1178-7031
DOI - 10.2147/jir.s367699
Subject(s) - trypsin , pancreatitis , gene isoform , chemistry , enzyme , biochemistry , trypsinogen , medicine , gene
The pathophysiological mechanisms underlying chronic pancreatitis (CP) are still poorly understood. Human cationic (TRY1) and anionic (TRY2) trypsins are the two major trypsin isoforms and their activities are tightly regulated within pancreatic acinar cells. Typically, they exist in a molar ratio of 2:1 (cationic:anionic). This ratio is reversed during chronic alcohol abuse, pancreatic cancer, or pancreatitis due to selectively upregulated expression of TRY2, causing anionic trypsin to become the predominant isoform. The involvement of TRY2 in pancreatitis is considered limited due to the absence of disease-causing mutations and its increased prevalence for autoproteolysis. However, exacerbated pancreatitis in TRY2 overexpressing mice was recently demonstrated. Here, we aim to elucidate the molecular structure of human anionic trypsin and obtain insights into the autoproteolytic regulation of tryptic activity.