ArticleBlood2020
PAR4 activation involves extracellular loop 3 and transmembrane residue Thr153.
Article in Blood, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Neutrophil cathepsin G potentiates biased signaling through protease-activated receptor 4.Blood advances · 2026Article
- Mice with reduced protease-activated receptor 4 reactivity show decreased venous thrombosis and platelet procoagulant activity.Journal of thrombosis and haemostasis : JTH · 2025Article
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- Mice with Reduced PAR4 Reactivity show Decreased Venous Thrombosis and Platelet Procoagulant Activity.bioRxiv : the preprint server for biology · 2024Article
- A mouse model of the protease-activated receptor 4 Pro310Leu variant has reduced platelet reactivity.Journal of thrombosis and haemostasis : JTH · 2024Article
- Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening.ACS pharmacology & translational science · 2024Article
- MicroRNA-26a alleviates tubulointerstitial fibrosis in diabetic kidney disease by targeting PAR4.Journal of cellular and molecular medicine · 2024Article
- An early warning indicator of mortality risk in patients with COVID-19: the neutrophil extracellular traps/neutrophilic segmented granulocyte ratio.Frontiers in immunology · 2024Article
- Species Differences in Platelet Protease-Activated Receptors.International journal of molecular sciences · 2023Review
- Mechanism of tethered agonist-mediated signaling by polycystin-1.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Neutrophil cathepsin G proteolysis of protease-activated receptor 4 generates a novel, functional tethered ligand.Blood advances · 2022Article
- A Role for Protease Activated Receptor Type 3 (PAR3) in Nociception Demonstrated Through Development of a Novel Peptide Agonist.The journal of pain · 2021Article
- Murine cadherin-6 mediates thrombosis in vivo in a platelet-independent manner.Research and practice in thrombosis and haemostasis · 2021Article
- Complement factor C4a does not activate protease-activated receptor 1 (PAR1) or PAR4 on human platelets.Research and practice in thrombosis and haemostasis · 2021Article
- The domino effect triggered by the tethered ligand of the protease activated receptors.Thrombosis research · 2020Review
- The Roles of GRKs in Hemostasis and Thrombosis.International journal of molecular sciences · 2020Review
- Advances in Understanding the Initial Steps of Pruritoceptive Itch: How the Itch Hits the Switch.International journal of molecular sciences · 2020Review
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7 authors at 2 institutions in 1 country.
Funding
Abstract
Protease-activated receptor 4 (PAR4) mediates sustained thrombin signaling in platelets and is required for a stable thrombus. PAR4 is activated by proteolysis of the N terminus to expose a tethered ligand. The structural basis for PAR4 activation and the location of its ligand binding site (LBS) are unknown. Using hydrogen/deuterium exchange (H/D exchange), computational modeling, and signaling studies, we determined the molecular mechanism for tethered ligand-mediated PAR4 activation. H/D exchange identified that the LBS is composed of transmembrane 3 (TM3) domain and TM7. Unbiased computational modeling further predicted an interaction between Gly48 from the tethered ligand and Thr153 from the LBS. Mutating Thr153 significantly decreased PAR4 signaling. H/D exchange and modeling also showed that extracellular loop 3 (ECL3) serves as a gatekeeper for the interaction between the tethered ligand and LBS. A naturally occurring sequence variant (P310L, rs2227376) and 2 experimental mutations (S311A and P312L) determined that the rigidity conferred by prolines in ECL3 are essential for PAR4 activation. Finally, we examined the role of the polymorphism at position 310 in venous thromboembolism (VTE) using the International Network Against Venous Thrombosis (INVENT) consortium multi-ancestry genome-wide association study (GWAS) meta-analysis. Individuals with the PAR4 Leu310 allele had a 15% reduction in relative risk for VTE (odds ratio, 0.85; 95% confidence interval, 0.77-0.94) compared with the Pro310 allele. These data are consistent with our H/D exchange, molecular modeling, and signaling studies. In conclusion, we have uncovered the structural basis for PAR4 activation and identified a previously unrecognized role for PAR4 in VTE.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.