Abstract
Protein C is a vitamin K-dependent anticoagulant serine protease zymogen in plasma which upon activation by the thrombin-thrombomodulin complex down-regulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. In addition to its anticoagulant function, activated protein C (APC) also binds to endothelial protein C receptor (EPCR) in lipid-rafts/caveolar compartments to activate protease- activated receptor 1 (PAR-1) thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells. These properties have led to FDA approval of recombinant APC as a therapeutic drug for severe sepsis. The mechanism by which APC selects its substrates in the anticoagulant and antiinflammatory pathways is not well understood. Recent structural and mutagenesis data have indicated that basic residues of three exposed surface loops known as 39-loop (Lys-37, Lys-38, and Lys-39), 60-loop (Lys-62, Lys- 63, and Arg-67), and 70-80-loop (Arg-74, Arg-75, and Lys-78) (chymotrypsin numbering) constitute an anion binding exosite in APC that interacts with the procoagulant cofactors Va and VIIIa in the anticoagulant pathway. Furthermore, two negatively charged residues on the opposite side of the active-site of APC on a helical structure have been demonstrated to determine the specificity of the PAR-1 recognition in the cytoprotective pathway. This article will review the mechanism by which APC exerts its proteolytic function in two physiologically inter-related pathways and how the structure- function insights into determinants of the specificity of APC interaction with its substrates in two pathways can be utilized to tinker with the structure of the molecule to obtain APC derivatives with potentially improved therapeutic profiles.
Keywords: APC, EPCR, PAR-1, Thrombomodulin, Anticoagulant, Antiinflammatory, Specificity
Current Medicinal Chemistry
Title: Regulation of the Protein C Anticoagulant and Antiinflammatory Pathways
Volume: 17 Issue: 19
Author(s): A.R. Rezaie
Affiliation:
Keywords: APC, EPCR, PAR-1, Thrombomodulin, Anticoagulant, Antiinflammatory, Specificity
Abstract: Protein C is a vitamin K-dependent anticoagulant serine protease zymogen in plasma which upon activation by the thrombin-thrombomodulin complex down-regulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. In addition to its anticoagulant function, activated protein C (APC) also binds to endothelial protein C receptor (EPCR) in lipid-rafts/caveolar compartments to activate protease- activated receptor 1 (PAR-1) thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells. These properties have led to FDA approval of recombinant APC as a therapeutic drug for severe sepsis. The mechanism by which APC selects its substrates in the anticoagulant and antiinflammatory pathways is not well understood. Recent structural and mutagenesis data have indicated that basic residues of three exposed surface loops known as 39-loop (Lys-37, Lys-38, and Lys-39), 60-loop (Lys-62, Lys- 63, and Arg-67), and 70-80-loop (Arg-74, Arg-75, and Lys-78) (chymotrypsin numbering) constitute an anion binding exosite in APC that interacts with the procoagulant cofactors Va and VIIIa in the anticoagulant pathway. Furthermore, two negatively charged residues on the opposite side of the active-site of APC on a helical structure have been demonstrated to determine the specificity of the PAR-1 recognition in the cytoprotective pathway. This article will review the mechanism by which APC exerts its proteolytic function in two physiologically inter-related pathways and how the structure- function insights into determinants of the specificity of APC interaction with its substrates in two pathways can be utilized to tinker with the structure of the molecule to obtain APC derivatives with potentially improved therapeutic profiles.
Export Options
About this article
Cite this article as:
Rezaie A.R., Regulation of the Protein C Anticoagulant and Antiinflammatory Pathways, Current Medicinal Chemistry 2010; 17 (19) . https://dx.doi.org/10.2174/092986710791233706
DOI https://dx.doi.org/10.2174/092986710791233706 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Thromboprophylaxis in Medical Patients: An Update
Vascular Disease Prevention (Discontinued) Prevention and treatment of atherosclerosis with flaxseed -derived compound secoisolariciresinol diglucoside
Current Pharmaceutical Design The Role of Integrin-Mediated Cell Adhesion in Atherosclerosis: Pathophysiology and Clinical Opportunities
Current Pharmaceutical Design Bioavailability of Quercetin: Problems and Promises
Current Medicinal Chemistry Catastrophic Antiphospholipid Syndrome: Lessons from the “CAPS Registry”
Current Rheumatology Reviews Coagulation Disorders in Acute Lung Injury
Current Respiratory Medicine Reviews Interatrial Block in the Modern Era
Current Cardiology Reviews Potential Advantages of Using Synchrotron X-ray Based Techniques in Pediatric Research
Current Medicinal Chemistry Editorial (Thematic Issue: Cardiac Imaging in the Diagnosis of Coronary Artery Disease: A Comprehensive Overview of Various Imaging Modalities)
Current Medical Imaging Nutritional Antioxidants and Adaptive Cell Responses: An Update
Current Molecular Medicine Steroidal Conjugates and Their Pharmacological Applications
Current Medicinal Chemistry The Use of Nitric Oxide Synthase Inhibitors in Inflammatory Diseases: A Novel Class of Anti-Inflammatory Agents
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Cyclodextrin Based Nanosponges: A Multidimensional Drug Delivery System and its Biomedical Applications
Current Drug Delivery Coumarin and Isocoumarin as Serine Protease Inhibitors
Current Pharmaceutical Design Apoptosis Signaling Pathways in Lung Diseases
Medicinal Chemistry Nanomaterials as Emerging Environmental Threats
Current Chemical Biology Recent Advancement in the Treatment of Cardiovascular Diseases: Conventional Therapy to Nanotechnology
Current Pharmaceutical Design Feasibility of Transcutaneous Method for Carbon Dioxide Monitoring in an Intensive Care Unit
Current Respiratory Medicine Reviews Effects of ACE Inhibitors on Skeletal Muscle
Current Pharmaceutical Design Absorption, Pharmacokinetics and Disposition Properties of Solid Lipid Nanoparticles (SLNs)
Current Drug Metabolism