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Title: Zymogen and activated protein C have similar structural architecture

Abstract

Activated protein C is a trypsin-like protease with anticoagulant and cytoprotective properties that is generated by thrombin from the zymogen precursor protein C in a reaction greatly accelerated by the cofactor thrombomodulin. The molecular details of this activation remain elusive due to the lack of structural information. We now fill this gap by providing information on the overall structural organization of these proteins using single molecule Förster resonance energy transfer and small angle X-ray scattering. Under physiological conditions, both zymogen and protease adopt a conformation with all domains vertically aligned along an axis 76 Å long and maximal particle size of 120 Å. This conformation is stabilized by binding of Ca2+ to the Gla domain and is affected minimally by interaction with thrombin. Hence, the zymogen protein C likely interacts with the thrombin-thrombomodulin complex through a rigid body association that produces a protease with essentially the same structural architecture. This scenario stands in contrast to an analogous reaction in the coagulation cascade where conversion of the zymogen prothrombin to the protease meizothrombin by the prothrombinase complex is linked to a large conformational transition of the entire protein. The presence of rigid EGF domains in protein C as opposed to kringlesmore » in prothrombin likely accounts for the different conformational plasticity of the two zymogens. The new structural features reported here for protein C have general relevance to vitamin K-dependent clotting factors containing EGF domains, such as factors VII, IX, and X.« less

Authors:
 [1];  [1];  [2]; ORCiD logo [1]
  1. Saint Louis Univ., St. Louis, MO (United States). School of Medicine
  2. Argonne National Lab. (ANL), Lemont, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1774125
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 295; Journal Issue: 45
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; BioSAXS; ligand-binding protein; protein C; protein conformation; serine protease; single molecule biophysics; thrombin

Citation Formats

Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, and Di Cera, Enrico. Zymogen and activated protein C have similar structural architecture. United States: N. p., 2020. Web. doi:10.1074/jbc.RA120.014789.
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, & Di Cera, Enrico. Zymogen and activated protein C have similar structural architecture. United States. https://doi.org/10.1074/jbc.RA120.014789
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, and Di Cera, Enrico. 2020. "Zymogen and activated protein C have similar structural architecture". United States. https://doi.org/10.1074/jbc.RA120.014789. https://www.osti.gov/servlets/purl/1774125.
@article{osti_1774125,
title = {Zymogen and activated protein C have similar structural architecture},
author = {Stojanovski, Bosko M. and Pelc, Leslie A. and Zuo, Xiaobing and Di Cera, Enrico},
abstractNote = {Activated protein C is a trypsin-like protease with anticoagulant and cytoprotective properties that is generated by thrombin from the zymogen precursor protein C in a reaction greatly accelerated by the cofactor thrombomodulin. The molecular details of this activation remain elusive due to the lack of structural information. We now fill this gap by providing information on the overall structural organization of these proteins using single molecule Förster resonance energy transfer and small angle X-ray scattering. Under physiological conditions, both zymogen and protease adopt a conformation with all domains vertically aligned along an axis 76 Å long and maximal particle size of 120 Å. This conformation is stabilized by binding of Ca2+ to the Gla domain and is affected minimally by interaction with thrombin. Hence, the zymogen protein C likely interacts with the thrombin-thrombomodulin complex through a rigid body association that produces a protease with essentially the same structural architecture. This scenario stands in contrast to an analogous reaction in the coagulation cascade where conversion of the zymogen prothrombin to the protease meizothrombin by the prothrombinase complex is linked to a large conformational transition of the entire protein. The presence of rigid EGF domains in protein C as opposed to kringles in prothrombin likely accounts for the different conformational plasticity of the two zymogens. The new structural features reported here for protein C have general relevance to vitamin K-dependent clotting factors containing EGF domains, such as factors VII, IX, and X.},
doi = {10.1074/jbc.RA120.014789},
url = {https://www.osti.gov/biblio/1774125}, journal = {Journal of Biological Chemistry},
number = 45,
volume = 295,
place = {United States},
year = {2020},
month = {11}
}

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