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TitleCryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 6955, Year 2022
Publish dateNov 14, 2022
AuthorsXiaoli Yang / Zhanyu Ding / Lisi Peng / Qiuyue Song / Deyu Zhang / Fang Cui / Chuanchao Xia / Keliang Li / Hua Yin / Shiyu Li / Zhaoshen Li / Haojie Huang /
PubMed AbstractEnteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of pancreatic diseases including ...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.
External linksNat Commun / PubMed:36376282 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 4.9 Å
Structure data

32714

7wqw

EMDB-32714, PDB-7wqw:
Structure of Active-EP
Method: EM (single particle) / Resolution: 3.2 Å

32715

7wqx

EMDB-32715, PDB-7wqx:
Structure of Inactive-EP
Method: EM (single particle) / Resolution: 2.7 Å

32716

7wqz

EMDB-32716, PDB-7wqz:
Structure of Active-mutEP
Method: EM (single particle) / Resolution: 3.7 Å

32717

7wr7

EMDB-32717, PDB-7wr7:
Structure of Inhibited-EP
Method: EM (single particle) / Resolution: 3.1 Å

32828

8h3u

EMDB-32828: Inhibited EP-complete
PDB-8h3u: Inhibitor-bound EP, polyA model
Method: EM (single particle) / Resolution: 4.7 Å

32829

8h3s

EMDB-32829: Substrate bound EP
PDB-8h3s: Substrate-bound EP, polyA model
Method: EM (single particle) / Resolution: 4.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-GBS:
4-carbamimidamidobenzoic acid / anticancer, anticoagulant, antivirus, protease inhibitor*YM / Nafamostat

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / COMPLEX / HYDROLASE / MEMBRANE PROTEIN/HYDROLASE / MEMBRANE PROTEIN-HYDROLASE complex

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