Hydrogen-deuterium exchange mass spectrometry highlights conformational changes induced by factor XI activation and binding of factor IX to factor XIa
© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis..
BACKGROUND: Factor XI (FXI) is a zymogen in the coagulation pathway that, once activated, promotes haemostasis by activating factor IX (FIX). Substitution studies using apple domains of the homologous protein prekallikrein have identified that FIX binds to the apple 3 domain of FXI. However, the molecular changes upon activation of FXI or binding of FIX to FXIa have remained largely unresolved.
OBJECTIVES: This study aimed to gain more insight in the FXI activation mechanism by identifying the molecular differences between FXI and FXIa, and in the conformational changes in FXIa induced by binding of FIX.
METHODS: Hydrogen-deuterium exchange mass spectrometry was performed on FXI, FXIa, and FXIa in complex with FIX.
RESULTS: Both activation and binding to FIX induced conformational changes at the interface between the catalytic domain and the apple domains of FXI(a)-more specifically at the loops connecting the apple domains. Moreover, introduction of FIX uniquely induced a reduction of deuterium uptake in the beginning of the apple 3 domain.
CONCLUSIONS: We propose that the conformational changes of the catalytic domain upon activation increase the accessibility to the apple 3 domain to enable FIX binding. Moreover, our HDX MS results support the location of the proposed FIX binding site at the beginning of the apple 3 domain and suggest a mediating role in FIX binding for both loops adjacent to the apple 3 domain.
| Errataetall: |
CommentIn: J Thromb Haemost. 2019 Dec;17(12):2016-2018. - PMID 31797540 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Journal of thrombosis and haemostasis : JTH - 17(2019), 12 vom: 28. Dez., Seite 2047-2055 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bar Barroeta, Awital [VerfasserIn] |
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| Links: |
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| Themen: |
9001-28-9 |
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| Anmerkungen: |
Date Completed 08.09.2020 Date Revised 29.08.2023 published: Print-Electronic CommentIn: J Thromb Haemost. 2019 Dec;17(12):2016-2018. - PMID 31797540 Citation Status MEDLINE |
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| doi: |
10.1111/jth.14632 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM301275750 |
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| 245 | 1 | 0 | |a Hydrogen-deuterium exchange mass spectrometry highlights conformational changes induced by factor XI activation and binding of factor IX to factor XIa |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: J Thromb Haemost. 2019 Dec;17(12):2016-2018. - PMID 31797540 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis. | ||
| 520 | |a BACKGROUND: Factor XI (FXI) is a zymogen in the coagulation pathway that, once activated, promotes haemostasis by activating factor IX (FIX). Substitution studies using apple domains of the homologous protein prekallikrein have identified that FIX binds to the apple 3 domain of FXI. However, the molecular changes upon activation of FXI or binding of FIX to FXIa have remained largely unresolved | ||
| 520 | |a OBJECTIVES: This study aimed to gain more insight in the FXI activation mechanism by identifying the molecular differences between FXI and FXIa, and in the conformational changes in FXIa induced by binding of FIX | ||
| 520 | |a METHODS: Hydrogen-deuterium exchange mass spectrometry was performed on FXI, FXIa, and FXIa in complex with FIX | ||
| 520 | |a RESULTS: Both activation and binding to FIX induced conformational changes at the interface between the catalytic domain and the apple domains of FXI(a)-more specifically at the loops connecting the apple domains. Moreover, introduction of FIX uniquely induced a reduction of deuterium uptake in the beginning of the apple 3 domain | ||
| 520 | |a CONCLUSIONS: We propose that the conformational changes of the catalytic domain upon activation increase the accessibility to the apple 3 domain to enable FIX binding. Moreover, our HDX MS results support the location of the proposed FIX binding site at the beginning of the apple 3 domain and suggest a mediating role in FIX binding for both loops adjacent to the apple 3 domain | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a factor IX | |
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| 650 | 4 | |a hemostasis | |
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| 700 | 1 | |a van Galen, Josse |e verfasserin |4 aut | |
| 700 | 1 | |a Stroo, Ingrid |e verfasserin |4 aut | |
| 700 | 1 | |a Marquart, J Arnoud |e verfasserin |4 aut | |
| 700 | 1 | |a Meijer, Alexander B |e verfasserin |4 aut | |
| 700 | 1 | |a Meijers, Joost C M |e verfasserin |4 aut | |
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