ArticleJournal of thrombosis and haemostasis : JTH2025
Structural determinants of protease-activated receptor 1 cleavage by activated protein C.
Article in Journal of thrombosis and haemostasis : JTH, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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Who cites it
2 citing papers in PubMed.
- Protease-Activated Receptor 1 as an Endogenous Model of Peptidergic Gαq-Gα12-Biased G Protein Signaling.bioRxiv : the preprint server for biology · 2026Article
- Protease-activated receptor 1 as an endogenous model of peptidergic Gαq-Gα12-biased G protein signaling.Frontiers in molecular biosciences · 2026Article
Corrections and comments
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Authors and funding
2 authors.
Funding
Abstract
backgroundActivated protein C (APC) performs cytoprotective functions mediated by cleavage of the protease-activated receptor 1 (PAR1) in the presence of the endothelial protein C receptor and signaling through β-arrestin-2. APC cleaves PAR1 at R41 and R46, but the specificity of the reaction is low. In contrast, thrombin cleaves PAR1 at R41 only in a reaction that is independent of endothelial protein C receptor, producing a proinflammatory response mediated by signaling through G-protein intermediates and features high specificity. The molecular basis of this difference between APC and thrombin remains unknown.
objectivesTo identify the structural determinants of APC that influence PAR1 specificity.
methodsUsing available structural information, we engineered thrombin determinants of PAR1 recognition into APC. Specifically, we replaced T99 with Leu and swapped the entire 37- and 60-loops of APC with those of thrombin (eg, APC
resultsThe engineered APC variants featured up to 80-fold enhanced specificity toward PAR1 mediated by increased cleavage at R41 and decreased cleavage at R46. Notably, the variants APC
conclusionThe 37, 60, and 99 segments of APC determine the cytoprotective and anticoagulant properties of the enzyme.
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