title: One-Way Allosteric Communication between the Two Disulfide Bonds in Tissue Factor.
abstract: 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.
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology (PICB), Shanghai, China; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Beifei
authors.initials: B
authors.lastname: Zhou
authors.affiliation: The Centenary Institute and National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hogg
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; University of Heidelberg, Interdisciplinary Center for Scientific Computing, Heidelberg, Germany. Electronic address: frauke.graeter@h-its.org.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001696:Biomechanical Phenomena; D004220:Disulfides / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D000072417:Protein Domains; D013925:Thromboplastin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D004220:Disulfides; D013925:Thromboplastin