ArticleThe Journal of biological chemistry2010
Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 64 citations in OpenAlex.
- Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9.The AAPS journal · 2015Trial
- The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol.Heart failure reviews · 2024Review
- The Multifaceted Biology of PCSK9.Endocrine reviews · 2022Review
- Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.Frontiers in physiology · 2022Article
- Strong relationship between cholesterol, low-density lipoprotein receptor, NaLipids in health and disease · 2021Article
- Impact of PCSK9 on CTRP9-Induced Metabolic Effects in Adult Rat Cardiomyocytes.Frontiers in physiology · 2021Article
- PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD).Advanced pharmaceutical bulletin · 2020Review
- A transient amphipathic helix in the prodomain of PCSK9 facilitates binding to low-density lipoprotein particles.The Journal of biological chemistry · 2020Article
- Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor).Arteriosclerosis, thrombosis, and vascular biology · 2019Article
- 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
- Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.Basic research in cardiology · 2017Review
- Selection of DNA aptamers with two modified bases.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Studies of the autoinhibitory segment comprising residues 31-60 of the prodomain of PCSK9: Possible implications for the mechanism underlying gain-of-function mutations.Molecular genetics and metabolism reports · 2016Article
- Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation.The Journal of biological chemistry · 2016Article
- Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain.PloS one · 2016Article
- Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other.The Journal of biological chemistry · 2015Article
- Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9).Basic research in cardiology · 2015Review
- PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells.Current opinion in lipidology · 2014Review
- Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
PCSK9, a target for the treatment of dyslipidemia, enhances the degradation of the LDL receptor (LDLR) in endosomes/lysosomes, up-regulating LDL-cholesterol levels. Whereas the targeting and degradation of the PCSK9-LDLR complex are under scrutiny, the roles of the N- and C-terminal domains of PCSK9 are unknown. Although autocatalytic zymogen processing of PCSK9 occurs at Gln(152)↓, here we show that human PCSK9 can be further cleaved in its N-terminal prosegment at Arg(46)↓ by an endogenous enzyme of insect High Five cells and by a cellular mammalian protease, yielding an ∼4-fold enhanced activity. Removal of the prosegment acidic stretch resulted in ∼3-fold higher binding to LDLR in vitro, in ≥4-fold increased activity on cellular LDLR, and faster cellular internalization in endosome/lysosome-like compartments. Finally, swapping the acidic stretch of PCSK9 with a similar one found in the glycosylphosphatidylinositol-anchored heparin-binding protein 1 does not impair PCSK9 autoprocessing, secretion, or activity and confirmed that the acidic stretch acts as an inhibitor of PCSK9 function. We also show that upon short exposure to pH values 6.5 to 5.5, an ∼2.5-fold increase in PCSK9 activity on total and cell surface LDLR occurs, and PCSK9 undergoes a second cleavage at Arg(248), generating a two-chain PCSK9-ΔN(248). At pH values below 5.5, PCSK9 dissociates from its prosegment and loses its activity. This pH-dependent activation of PCSK9 represents a novel pathway to further activate PCSK9 in acidic endosomes. These data enhance our understanding of the functional role of the acidic prosegment and on the effect of pH in the regulation of PCSK9 activity.
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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.