Structural insight into the CUB2 domain’s role in enteropeptidase-mediated trypsinogen activation
Abstract
Elucidating the structure and function of enteropeptidase (EP) is essential for advancing our understanding of its biological significance, particularly in regulating trypsinogen activation. Using cryo-EM and enzymatic activity, we uncovered the significance of the CUB2 domain in mediating the cleavage of macromolecular substrates. We identified crucial binding loops and key residues for EP’s proteolytic function. The mutation E574A enhanced the proteolytic activity of EP, whereas the mutation N619A diminished its cleavage efficiency, highlighting the importance of surface-charged interactions in modulating EP’s activity. A proteolytic cycle was proposed to deepen our understanding of the trypsinogen activation by EP. This work offers valuable insights into the molecular mechanisms underlying EP’s interaction with its substrate, and opens up avenues for therapeutically modulating EP-mediated proteolysis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Qiuyue Song
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Lisi Peng
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Xiaoli Yang
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Jiaheng Xu
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Deyu Zhang
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Xiaorong Tian
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Shiyu Li
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Yang Zhang
Baoan Ji
Department of Cancer Biology, Mayo Clinic in Florida
Zhendong Jin
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Zhanyu Ding
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Zhaoshen Li
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Haojie Huang
Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine