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Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors
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The PCSK9 C terminal domain binds the extracellular ligand binding domain of LDLR at low pH (pH < 5.4).
“The PCSK9 C terminal domain has been shown to bind the extracellular ligand binding domain of LDLR at low pH (pH < 5.4).”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [128]
The Far Western blot analysis section reports that the PCSK9 C-terminal domain binds the LDLR ligand-binding domain, particularly at low pH. The paper does not establish pH < 5.4 as the condition for that specific interaction: it describes pH 5.4 as endosomal pH, while its pH 5 experiments test binding of whole PCSK9 to LDLR. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe C terminal domain of PCSK9 is not required for PCSK9 to bind and be internalized by LDLR, but appears to be required for PCSK9 to disrupt recycling of LDLR back to the cell surface.
“The C terminal domain of PCSK9 is also not required for PCSK9 to bind and be internalized by LDLR, it appears to be required for PCSK9 to disrupt recycling of LDLR back to the cell surface126,128.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [128]
The introductory passage labeled Abstract says that PCSK9 lacking the C-terminal domain can bind LDLR but has little or no ability to mediate its degradation. The discussion in “Effect of replacing the C-terminal domain with an unrelated protein” proposes that a C-terminal structure interferes with LDLR sorting into recycling tubules, while leaving the exact mechanism unresolved. Our copy says that PCSK9 is internalized with LDLR, but does not establish that PCSK9 lacking the C-terminal domain is internalized with it. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe large number of histidines in the C terminal domain of PCSK9 gain a net increased positive charge at low pH, allowing increased affinity for the negatively charged ligand binding domain of LDLR.
“This is likely due to the large number of histidines in the C terminal domain of PCSK9 which gain a net increased positive charge at low pH. This allows them to have increased affinity for the negatively charged ligand binding domain of LDLR122,128,129.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [128]
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Research works printed but not linked: 21
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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
Targeting PCSK9 for hypercholesterolemia
Norata, G. D., Tibolla, G., & Catapano, A. L. (2014) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011613-140025 · Cited by 127
PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum
Strøm, T. B., Tveten, K., & Leren, T. P. (2014) · Biochemical Journal · doi:10.1042/bj20130930 · Cited by 48
Self-citationPathways and Molecular Mechanisms Governing LDL Receptor Regulation
Schmidt, H. M., Jarrett, K. E., de Aguiar Vallim, T. Q., & Tarling, E. J. (2025) · Circulation Research · doi:10.1161/circresaha.124.323578 · Cited by 33
Metadata
- Authors
- Holla, Ø. L., Cameron, J., Tveten, K., Str⊘m, T. B., Berge, K. E., Laerdahl, J. K., & Leren, T. P.
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 52
- Issue
- 10
- Pages
- 1787-1794
- ISSN
- 0022-2275
- Cited by
- 64
- References
- 0
- Language
- en
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