ArticleThe Journal of biological chemistry2014
The proprotein convertase subtilisin/kexin type 9 (PCSK9) active site and cleavage sequence differentially regulate protein secretion from proteolysis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The trial behind it
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Applications of synthetic biology in biomedicine.Molecular biomedicine · 2026Review
- PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Link between miRNAs and PCKS9 in Atherosclerosis.Current medicinal chemistry · 2024Review
- PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity.Journal of experimental & clinical cancer research : CR · 2023Article
- The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases.Metabolites · 2022Review
- The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury.The Journal of clinical investigation · 2021Article
- Current Evidence and Future Directions of PCSK9 Inhibition.US cardiology · 2021Review
- Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies.Cardiovascular research · 2019Review
- Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake.Journal of lipid research · 2019Article
- A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9.Journal of visualized experiments : JoVE · 2018Article
- Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype.The Journal of biological chemistry · 2018Article
- Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries.Frontiers in cardiovascular medicine · 2018Review
- The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol.Global cardiology science & practice · 2017Review
- Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives.Acta pharmacologica Sinica · 2017Review
- Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism.The Journal of biological chemistry · 2017Article
- Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor.Protein science : a publication of the Protein Society · 2016Article
- Suppressor of Cytokine Signaling-3 (SOCS-3) Induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Expression in Hepatic HepG2 Cell Line.The Journal of biological chemistry · 2016Article
- PCSK9 inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9.Current opinion in endocrinology, diabetes, and obesity · 2015Review
- Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9).Basic research in cardiology · 2015Review
- Atherosclerosis: cell biology and lipoproteins.Current opinion in lipidology · 2013Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Biologic-based strategies to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) show promise as anti-hypercholesterolemic and, therefore, anti-atherosclerotic therapies. Despite substantial effort, no small molecule strategy to inhibit PCSK9 has demonstrated feasibility. In this study we interrogated the chemistry of the PCSK9 active site and its adjacent residues to identify a foothold with which to drug the PCSK9 processing pathway and ultimately disrupt the interaction with the LDL receptor. Here, we develop a system in which we amplify the readout of PCSK9 proteolysis with a highly specific substrate in cells, showing that the PCSK9 catalytic domain is capable of proteolysis in trans. We use this system to show that the substrate specificity for PCSK9 proteolysis is distinct from the specificity for PCSK9 secretion, demonstrating that PCSK9 processing occurs in two separate sequential steps: that of proteolysis followed by secretion. We show that specific residues in the protease recognition sequence can differentially modulate the effects on proteolysis and secretion. Additionally, we demonstrate that the clinically described, dominant negative Q152H mutation restricts proteolysis and secretion independently. Our results suggest that the PCSK9 active site and its adjacent residues serve as an allosteric modulator of protein secretion independent of its role in proteolysis, revealing a new strategy for intracellular PCSK9 inhibition.
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What OpenQuestion holds
Registered trials
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.