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Cited by 99Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor

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Duff, Christopher J., Scott, Martin J., Kirby, Ian T., Hutchinson, Sue E., Martin, Steve L., Hooper, Nigel M.·2009·Biochemical Journal
DOI 10.1042/bj20082407PMC PMC2669217
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Abstract

PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes degradation of the LDLR [LDL (low-density lipoprotein) receptor] through an as-yet-undefined mechanism, leading to a reduction in cellular LDLc (LDL-cholesterol) and a concomitant increase in serum LDLc. Central to the function of PCSK9 is a direct protein–protein interaction formed with the LDLR. In the present study, we investigated a strategy to modulate LDL uptake by blocking this interaction using specific antibodies directed against PCSK9. Studies using surface plasmon resonance demonstrated that direct binding of PCSK9 to the LDLR could be abolished with three different anti-PCSK9 antibodies. Two of these antibodies were raised against peptide epitopes in a region of the catalytic domain of PCSK9 that is involved in the interaction with the LDLR. Such antibodies restored LDL uptake in HepG2 cells treated with exogenous PCSK9 and in HepG2 cells engineered to overexpress recombinant PCSK9. This latter observation indicates that antibodies blocking the PCSK9–LDLR interaction can inhibit the action of PCSK9 produced endogenously in a cell-based system. These antibodies also disrupted the higher-affinity interaction between the natural gain-of-function mutant of PCSK9, D374Y, and the LDLR in both the cell-free and cell-based assays. These data indicate that antibodies targeting PCSK9 can reverse the PCSK9-mediated modulation of cell-surface LDLRs.

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  • Deletions of the M1, M3, and aa367-386 domains of PCSK9 showed reduced H2-K1 binding.

    “deletions of the other two domains (M1 & M3) and the aa367–386 domain, which was involved in LDLR binding34, in the catalytic region, also showed reduced H2-K1 binding”

    From Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer (2020) · cites this paper as [34]

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Authors
Duff, C. J., Scott, M. J., Kirby, I. T., Hutchinson, S. E., Martin, S. L., & Hooper, N. M.
Affiliations
  • University of Leeds (GB)
  • GlaxoSmithKline (United Kingdom) (GB)
Corresponding author
Hooper, Nigel M.
ORCID
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2009-04-14
Volume
419
Issue
3
Pages
577-584
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj20082407
PMC
PMC2669217
OpenAlex
W1988805720
Cited by
99
References
0
Citations by year
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FWCI
14.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Journal (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
Funders
  • Directorate for Biological Sciences
  • Biotechnology and Biological Sciences Research Council
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
PCSK9, LDL receptor, LDL uptake, LDL cholesterol, PCSK9 inhibitors
MeSH terms
Proprotein Convertase 9, Animals, Antibodies, Epitopes, Cell Line, Extracellular Space, Humans, Insecta, Kinetics, Cholesterol, LDL, Models, Molecular, Protein Binding, Receptors, LDL, Serine Endopeptidases, Reproducibility of Results, Proprotein Convertases, Mutant Proteins

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