PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) and induces its internalization and degradation. PCSK9 binding to LDLR is mediated through the LDLR epidermal growth factor-like repeat A (EGF-A) domain. We show for the first time that an EGF-A peptide inhibits PCSK9-mediated degradation of LDLR in HepG2 cells. In addition to LDLR, we show that PCSK9 also binds directly to ApoER2 and mouse VLDLR. Importantly, binding of PCSK9 to either LDLR or mouse VLDLR was effectively inhibited by EGF-A while binding to ApoER2 was less affected. In contrast, LDL receptor-associated protein (RAP), which interacts with LDL receptor repeat type A (LA) domains, inhibited PCSK9 binding to ApoER2 with greater efficacy than either LDLR or mVLDLR. These data demonstrate that while PCSK9 binds several receptors via its EGF-A binding domain, additional contacts with other receptor domains are also involved.
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PCSK9 post-translationally modulates the levels of LDLR, VLDLR, and ApoER2.
“Similar to IDOL, the secreted protein PCSK9 also post-translationally modulates the levels of the LDLR, VLDLR, and ApoER2 (26, 27).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [27]
PCSK9 is a secreted protein that binds the ecto-domain of the receptors and promotes their endocytosis and lysosomal degradation.
“PCSK9 is a secreted protein that binds the ecto-domain of the receptors and promotes their endocytosis and lysosomal degradation.”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [27]
The substrate specificities of IDOL and PCSK9 overlap.
“Our results further indicate that the substrate specificities of IDOL and PCSK9 overlap, because previous studies have suggested that PCSK9 can also reduce the protein levels of VLDLR and ApoER2 (26, 27).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [27]
PCSK9 binds to LDLR, VLDLR, and ApoER2 and promotes their degradation in intracellular acidic compartments.
“The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments.”
From PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling (2012) · cites this paper as [6]
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Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer
Liu, X., Bao, X., Hu, M., Chang, H., Jiao, M., Cheng, J., Xie, L., Huang, Q., Li, F., & Li, C.-Y. (2020) · Nature · doi:10.1038/s41586-020-2911-7 · Cited by 490 · see citing works
Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): From bench to bedside
Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187 · see citing works
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PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling
Kysenius, K., Muggalla, P., Mätlik, K., Arumäe, U., & Huttunen, H. J. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-0977-6 · Cited by 137 · see citing works
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Insight into the Evolving Role of PCSK9
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“Some of them are also able to block PCSK9 interaction with VLDLR and less effectively with ApoER2 [149–151].”
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- Authors
- Shan, L., Pang, L., Zhang, R., Murgolo, N. J., Lan, H., & Hedrick, J. A.
- Corresponding author
- Hedrick, Joseph A.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 375
- Issue
- 1
- Pages
- 69-73
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2087956853
- Cited by
- 180
- References
- 1
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 12 · 2019: 11 · 2018: 16 · 2017: 14 · 2016: 12 · 2015: 10 · 2014: 13 · 2013: 16 · 2012: 11
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- 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, ApoER2, VLDLR, receptor internalization, receptor degradation, receptor binding
- MeSH terms
- Proprotein Convertase 9, Animals, Cell Line, Epidermal Growth Factor, Humans, Peptides, Receptors, LDL, Serine Endopeptidases, Protein Structure, Tertiary, Receptors, Lipoprotein, LDL-Receptor Related Proteins, Proprotein Convertases, Mice
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