Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase

Xiaoli Yang, Zhanyu Ding, Lisi Peng, Qiuyue Song, Deyu Zhang, Fang Cui, Chuanchao Xia, Keliang Li, Hua Yin, Shiyu Li, Zhaoshen Li () and Haojie Huang ()
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Xiaoli Yang: Navy/Second Military Medical University
Zhanyu Ding: Navy/Second Military Medical University
Lisi Peng: Navy/Second Military Medical University
Qiuyue Song: Navy/Second Military Medical University
Deyu Zhang: Navy/Second Military Medical University
Fang Cui: Navy/Second Military Medical University
Chuanchao Xia: Navy/Second Military Medical University
Keliang Li: Navy/Second Military Medical University
Hua Yin: Navy/Second Military Medical University
Shiyu Li: Navy/Second Military Medical University
Zhaoshen Li: Navy/Second Military Medical University
Haojie Huang: Navy/Second Military Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract Enteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of pancreatic diseases including acute necrotizing pancreatitis. However, the molecular mechanisms of EP activation and substrate recognition remain elusive, due to the lack of structural information on the EP heavy chain. Here, we report cryo-EM structures of human EP in inactive, active, and substrate-bound states at resolutions from 2.7 to 4.9 Å. The EP heavy chain was observed to clamp the light chain with CUB2 domain for substrate recognition. The EP light chain N-terminus induced a rearrangement of surface-loops from inactive to active conformations, resulting in activated EP. The heavy chain then served as a hinge for light-chain conformational changes to recruit and subsequently cleave substrate. Our study provides structural insights into rearrangements of EP surface-loops and heavy chain dynamics in the EP catalytic cycle, advancing our understanding of EP-associated pancreatitis.

Date: 2022
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DOI: 10.1038/s41467-022-34364-9

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