Enhancing the anticoagulant profile of meizothrombin
Abstract
Meizothrombin is an active intermediate generated during the proteolytic activation of prothrombin to thrombin in the penultimate step of the coagulation cascade. Structurally, meizothrombin differs from thrombin because it retains the auxiliary Gla domain and two kringles. Functionally, meizothrombin shares with thrombin the ability to cleave procoagulant (fibrinogen), prothrombotic (PAR1) and anticoagulant (protein C) substrates, although its specificity toward fibrinogen and PAR1 is less pronounced. In this study we report information on the structural architecture of meizothrombin resolved by SAXS and single molecule FRET as an elongated arrangement of its individual domains. In addition, we show the properties of a meizothrombin construct analogous to the anticoagulant thrombin mutant W215A/E217A currently in Phase I for the treatment of thrombotic complications and stroke. The findings reveal new structural and functional aspects of meizothrombin that advance our understanding of a key intermediate of the prothrombin activation pathway.
- Authors:
-
- Saint Louis Univ. School of Medicine, St. Louis, MO (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); American Heart Association; National Institutes of Health (NIH)
- OSTI Identifier:
- 1504767
- Grant/Contract Number:
- AC02-06CH11357; 15SDG25550094; HL049413; HL139554
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Biomolecular Concepts
- Additional Journal Information:
- Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 1868-5021
- Publisher:
- de Gruyter
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; enzxyme specificity; protein engineering; thrombin
Citation Formats
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, Pozzi, Nicola, and Cera, Enrico Di. Enhancing the anticoagulant profile of meizothrombin. United States: N. p., 2018.
Web. doi:10.1515/bmc-2018-0016.
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, Pozzi, Nicola, & Cera, Enrico Di. Enhancing the anticoagulant profile of meizothrombin. United States. https://doi.org/10.1515/bmc-2018-0016
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, Pozzi, Nicola, and Cera, Enrico Di. Wed .
"Enhancing the anticoagulant profile of meizothrombin". United States. https://doi.org/10.1515/bmc-2018-0016. https://www.osti.gov/servlets/purl/1504767.
@article{osti_1504767,
title = {Enhancing the anticoagulant profile of meizothrombin},
author = {Stojanovski, Bosko M. and Pelc, Leslie A. and Zuo, Xiaobing and Pozzi, Nicola and Cera, Enrico Di},
abstractNote = {Meizothrombin is an active intermediate generated during the proteolytic activation of prothrombin to thrombin in the penultimate step of the coagulation cascade. Structurally, meizothrombin differs from thrombin because it retains the auxiliary Gla domain and two kringles. Functionally, meizothrombin shares with thrombin the ability to cleave procoagulant (fibrinogen), prothrombotic (PAR1) and anticoagulant (protein C) substrates, although its specificity toward fibrinogen and PAR1 is less pronounced. In this study we report information on the structural architecture of meizothrombin resolved by SAXS and single molecule FRET as an elongated arrangement of its individual domains. In addition, we show the properties of a meizothrombin construct analogous to the anticoagulant thrombin mutant W215A/E217A currently in Phase I for the treatment of thrombotic complications and stroke. The findings reveal new structural and functional aspects of meizothrombin that advance our understanding of a key intermediate of the prothrombin activation pathway.},
doi = {10.1515/bmc-2018-0016},
journal = {Biomolecular Concepts},
number = 1,
volume = 9,
place = {United States},
year = {Wed Dec 26 00:00:00 EST 2018},
month = {Wed Dec 26 00:00:00 EST 2018}
}
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Figure 1: Solution structures of prothrombin and Mz revealed by SAXS and smFRET measurements. (A) Reconstructed 3D envelopes of prothrombin (red) and Mz (blue) calculated from their respective scattering profiles. The maximal particle sizes (Dmax) for prothrombin and Mz calculated from the pair distance distribution functions (not shown) are 120more »
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