One-way allosteric communication between the two disulfide bonds in tissue factor
Tissue factor (TF) is a transmembrane glycoprotein that plays distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. TF contains two disulfide bonds, one each in the N-terminal and C-terminal extracellular domains. The C-domain disulfide, Cys186-Cys209, has a −RHStaple con...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
10 January 2017
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| In: |
Biophysical journal
Year: 2017, Volume: 112, Issue: 1, Pages: 78-86 |
| ISSN: | 1542-0086 |
| DOI: | 10.1016/j.bpj.2016.12.003 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.bpj.2016.12.003 Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S0006349516342771 
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| Author Notes: | Beifei Zhou, Philip J. Hogg, and Frauke Gräter |
| Summary: | Tissue factor (TF) is a transmembrane glycoprotein that plays distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. TF contains two disulfide bonds, one each in the N-terminal and C-terminal extracellular domains. The C-domain disulfide, Cys186-Cys209, has a −RHStaple configuration in crystal structures, suggesting that this disulfide carries high pre-stress. The redox state of this disulfide has been proposed to regulate TF encryption/decryption. Ablating the N-domain Cys49-Cys57 disulfide bond was found to increase the redox potential of the Cys186-Cys209 bond, implying an allosteric communication between the domains. Using molecular dynamics simulations, we observed that the Cys186-Cys209 disulfide bond retained the −RHStaple configuration, whereas the Cys49-Cys57 disulfide bond fluctuated widely. The Cys186-Cys209 bond featured the typical −RHStaple disulfide properties, such as a longer S-S bond length, larger C-S-S angles, and higher bonded prestress, in comparison to the Cys49-Cys57 bond. Force distribution analysis was used to sense the subtle structural changes upon ablating the disulfide bonds, and allowed us to identify a one-way allosteric communication mechanism from the N-terminal to the C-terminal domain. We propose a force propagation pathway using a shortest-pathway algorithm, which we suggest is a useful method for searching allosteric signal transduction pathways in proteins. As a possible explanation for the pathway being one-way, we identified a pronounced lower degree of conformational fluctuation, or effectively higher stiffness, in the N-terminal domain. Thus, the changes of the rigid domain (N-terminal domain) can induce mechanical force propagation to the soft domain (C-terminal domain), but not vice versa. |
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| Item Description: | Gesehen am 06.08.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1542-0086 |
| DOI: | 10.1016/j.bpj.2016.12.003 |