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Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor

Zhang, Da-Wei, Garuti, Rita, Tang, Wan-Jin, Cohen, Jonathan C., Hobbs, Helen H.·2008·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0806312105
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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that controls plasma LDL cholesterol levels by posttranslational regulation of the LDL receptor (LDLR). Previously, we showed that PCSK9 binds specifically to an EGF-like repeat (EGF-A) in LDLR and reroutes the receptor from endosomes to lysosomes rather than to the cell surface. Here, we defined the regions in LDLR and PCSK9 that are required for receptor degradation and examined the relationship between PCSK9 binding and LDLR conformation. Addition of PCSK9 to cultured hepatocytes promoted degradation of WT LDLR and of receptors lacking up to four ligand binding domains, EGF-B or the clustered O-linked sugar region. In contrast, LDLRs lacking the entire ligand binding domain or the β-propeller domain failed to be degraded, although they bound and internalized PCSK9. Using gel filtration chromatography, we assessed the effects of PCSK9 binding on an acid-dependent conformational change that happens in the extracellular domain of the LDLR. Although PCSK9 prevented the reduction in hydrodynamic radius of the receptor that occurs at a reduced pH, the effect was not sufficient for LDLR degradation. A truncated version of PCSK9 containing the prodomain and the catalytic domain, but not the C-terminal domain, bound the receptor but did not stimulate LDLR degradation. Thus, domains in both the LDLR and PCSK9 that are not required for binding (or internalization) are essential for PCSK9-mediated degradation of the LDLR.

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  • PCSK9 prevents LDLR recycling and reduces ApoE uptake.

    “The activity of LDLR is tightly regulated by PCSK9, as it prevents its recycling to the surface and subsequently reduces ApoE uptake [31][32][33] .”

    From ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction (2026) · cites this paper as [32]

  • An LDLR lacking the ligand binding domain is able to internalize PCSK9 but is not degraded and instead recycles back to the plasma membrane.

    “A series of deletion studies demonstrate that an LDLR lacking the ligand binding domain is able to internalize PCSK9 but is not degraded and instead recycles back to the plasma membrane126,127.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [127]

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Research works printed but not linked: 34

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Metadata

Authors
Zhang, D.-W., Garuti, R., Tang, W.-J., Cohen, J. C., & Hobbs, H. H.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2008-09-02
Volume
105
Issue
35
Pages
13045-13050
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0806312105
Cited by
208
References
3
Language
en

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