Streptococcus co-opts a conformational lock in human plasminogen to facilitate streptokinase cleavage and bacterial virulence
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved..
Virulent strains of Streptococcus pyogenes (gram-positive group A Streptococcus pyogenes [GAS]) recruit host single-chain human plasminogen (hPg) to the cell surface-where in the case of Pattern D strains of GAS, hPg binds directly to the cells through a surface receptor, plasminogen-binding group A streptococcal M-protein (PAM). The coinherited Pattern D GAS-secreted streptokinase (SK2b) then accelerates cleavage of hPg at the R561-V562 peptide bond, resulting in the disulfide-linked two-chain protease, human plasmin (hPm). hPm localizes on the bacterial surface, assisting bacterial dissemination via proteolysis of host defense proteins. Studies using isolated domains from PAM and hPg revealed that the A-domain of PAM binds to the hPg kringle-2 module (K2hPg), but how this relates to the function of the full-length proteins is unclear. Herein, we use intact proteins to show that the lysine-binding site of K2hPg is a major determinant of the activation-resistant T-conformation of hPg. The binding of PAM to the lysine-binding site of K2hPg relaxes the conformation of hPg, leading to a greatly enhanced activation rate of hPg by SK2b. Domain swapping between hPg and mouse Pg emphasizes the importance of the Pg latent heavy chain (residues 1-561) in PAM binding and shows that while SK2b binds to both hPg and mouse Pg, the activation properties of streptokinase are strictly attributed to the serine protease domain (residues 562-791) of hPg. Overall, these data show that native hPg is locked in an activation-resistant conformation that is relaxed upon its direct binding to PAM, allowing hPm to form and provide GAS cells with a proteolytic surface.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:296 |
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| Enthalten in: |
The Journal of biological chemistry - 296(2021) vom: 01. Jan., Seite 100099 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ayinuola, Yetunde A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.08.2021 Date Revised 02.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA120.016262 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM317756346 |
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| 041 | |a eng | ||
| 100 | 1 | |a Ayinuola, Yetunde A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Streptococcus co-opts a conformational lock in human plasminogen to facilitate streptokinase cleavage and bacterial virulence |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 24.08.2021 | ||
| 500 | |a Date Revised 02.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Virulent strains of Streptococcus pyogenes (gram-positive group A Streptococcus pyogenes [GAS]) recruit host single-chain human plasminogen (hPg) to the cell surface-where in the case of Pattern D strains of GAS, hPg binds directly to the cells through a surface receptor, plasminogen-binding group A streptococcal M-protein (PAM). The coinherited Pattern D GAS-secreted streptokinase (SK2b) then accelerates cleavage of hPg at the R561-V562 peptide bond, resulting in the disulfide-linked two-chain protease, human plasmin (hPm). hPm localizes on the bacterial surface, assisting bacterial dissemination via proteolysis of host defense proteins. Studies using isolated domains from PAM and hPg revealed that the A-domain of PAM binds to the hPg kringle-2 module (K2hPg), but how this relates to the function of the full-length proteins is unclear. Herein, we use intact proteins to show that the lysine-binding site of K2hPg is a major determinant of the activation-resistant T-conformation of hPg. The binding of PAM to the lysine-binding site of K2hPg relaxes the conformation of hPg, leading to a greatly enhanced activation rate of hPg by SK2b. Domain swapping between hPg and mouse Pg emphasizes the importance of the Pg latent heavy chain (residues 1-561) in PAM binding and shows that while SK2b binds to both hPg and mouse Pg, the activation properties of streptokinase are strictly attributed to the serine protease domain (residues 562-791) of hPg. Overall, these data show that native hPg is locked in an activation-resistant conformation that is relaxed upon its direct binding to PAM, allowing hPm to form and provide GAS cells with a proteolytic surface | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a M-protein | |
| 650 | 4 | |a S. pyogenes | |
| 650 | 4 | |a bacterial virulence | |
| 650 | 4 | |a conformational change | |
| 650 | 4 | |a ligand binding | |
| 650 | 4 | |a plasminogen | |
| 650 | 4 | |a protein domains | |
| 650 | 4 | |a protein interactions | |
| 650 | 4 | |a streptokinase | |
| 650 | 7 | |a Bacterial Proteins |2 NLM | |
| 650 | 7 | |a Plasminogen |2 NLM | |
| 650 | 7 | |a 9001-91-6 |2 NLM | |
| 650 | 7 | |a Streptokinase |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 700 | 1 | |a Brito-Robinson, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Ayinuola, Olawole |e verfasserin |4 aut | |
| 700 | 1 | |a Beck, Julia E |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz-Topete, Diana |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Shaun W |e verfasserin |4 aut | |
| 700 | 1 | |a Ploplis, Victoria A |e verfasserin |4 aut | |
| 700 | 1 | |a Castellino, Francis J |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1074/jbc.RA120.016262 |3 Volltext |
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