Design and characterization of novel activated protein C variants for the proteolysis of cytotoxic extracellular histone H3
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
BACKGROUND: Extracellular histone H3 is implicated in several pathologies including inflammation, cell death, and organ failure. Neutralization of histone H3 is a strategy that was shown beneficial in various diseases, such as rheumatoid arthritis, myocardial infarction, and sepsis. It was shown that activated protein C (APC) can cleave histone H3, which reduces histone cytotoxicity. However, due to the anticoagulant properties of APC, the use of APC is not optimal for the treatment of histone-mediated cytotoxicity, in view of its associated bleeding side effects.
OBJECTIVES: This study aimed to investigate the detailed molecular interactions between human APC and human histone H3, and subsequently use molecular docking and molecular dynamics simulation methods to identify key interacting residues that mediate the interaction between APC and histone H3 and to generate novel optimized APC variants.
METHODS: After molecular simulations, the designed APC variants 3D2D-APC (Lys37-39Asp and Lys62-63Asp) and 3D2D2A-APC (Lys37-39Asp, Lys62-63Asp, and Arg74-75Ala) were recombinantly expressed and their abilities to function as anticoagulant, to bind histones, and to cleave histones were tested and correlated with their cytoprotective properties.
RESULTS: Compared with wild type-APC, both the 3D2D-APC and 3D2D2A-APC variants showed a significantly decreased anticoagulant activity, increased binding to histone H3, and similar ability to proteolyze histone H3.
CONCLUSIONS: Our data show that it is possible to rationally design APC variants that may be further developed into therapeutic biologicals to treat histone-mediated disease, by proteolytic reduction of histone-associated cytotoxic properties that do not induce an increased bleeding risk.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Journal of thrombosis and haemostasis : JTH - 21(2023), 12 vom: 08. Dez., Seite 3557-3567 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huckriede, Joram B [VerfasserIn] |
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| Links: |
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| Themen: |
Activated protein C (APC) |
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| Anmerkungen: |
Date Completed 15.12.2023 Date Revised 20.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jtha.2023.08.023 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Huckriede, Joram B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design and characterization of novel activated protein C variants for the proteolysis of cytotoxic extracellular histone H3 |
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| 500 | |a Date Revised 20.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Extracellular histone H3 is implicated in several pathologies including inflammation, cell death, and organ failure. Neutralization of histone H3 is a strategy that was shown beneficial in various diseases, such as rheumatoid arthritis, myocardial infarction, and sepsis. It was shown that activated protein C (APC) can cleave histone H3, which reduces histone cytotoxicity. However, due to the anticoagulant properties of APC, the use of APC is not optimal for the treatment of histone-mediated cytotoxicity, in view of its associated bleeding side effects | ||
| 520 | |a OBJECTIVES: This study aimed to investigate the detailed molecular interactions between human APC and human histone H3, and subsequently use molecular docking and molecular dynamics simulation methods to identify key interacting residues that mediate the interaction between APC and histone H3 and to generate novel optimized APC variants | ||
| 520 | |a METHODS: After molecular simulations, the designed APC variants 3D2D-APC (Lys37-39Asp and Lys62-63Asp) and 3D2D2A-APC (Lys37-39Asp, Lys62-63Asp, and Arg74-75Ala) were recombinantly expressed and their abilities to function as anticoagulant, to bind histones, and to cleave histones were tested and correlated with their cytoprotective properties | ||
| 520 | |a RESULTS: Compared with wild type-APC, both the 3D2D-APC and 3D2D2A-APC variants showed a significantly decreased anticoagulant activity, increased binding to histone H3, and similar ability to proteolyze histone H3 | ||
| 520 | |a CONCLUSIONS: Our data show that it is possible to rationally design APC variants that may be further developed into therapeutic biologicals to treat histone-mediated disease, by proteolytic reduction of histone-associated cytotoxic properties that do not induce an increased bleeding risk | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a activated protein C (APC) | |
| 650 | 4 | |a computer simulation | |
| 650 | 4 | |a extracellular traps | |
| 650 | 4 | |a histones | |
| 650 | 4 | |a sepsis | |
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| 650 | 7 | |a Histones |2 NLM | |
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| 700 | 1 | |a Beurskens, Daniëlle M H |e verfasserin |4 aut | |
| 700 | 1 | |a Wildhagen, Karin C C A |e verfasserin |4 aut | |
| 700 | 1 | |a Reutelingsperger, Chris P M |e verfasserin |4 aut | |
| 700 | 1 | |a Wichapong, Kanin |e verfasserin |4 aut | |
| 700 | 1 | |a Nicolaes, Gerry A F |e verfasserin |4 aut | |
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