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The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia

Cunningham, David, Danley, Dennis E, Geoghegan, Kieran F, Griffor, Matthew C, Hawkins, Julie L, Subashi, Timothy A, Varghese, Alison H, Ammirati, Mark J, Culp, Jeffrey S, Hoth, Lise R, Mansour, Mahmoud N, McGrath, Katherine M, Seddon, Andrew P, Shenolikar, Shirish, Stutzman-Engwall, Kim J, Warren, Laurie C, Xia, Donghui, Qiu, Xiayang·2007·Nature Structural & Molecular Biology
DOI 10.1038/nsmb1235
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Abstract

Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance of surface low-density lipoprotein (LDL) receptor through an undefined mechanism. The structure of human PCSK9 shows the subtilisin-like catalytic site blocked by the prodomain in a noncovalent complex and inaccessible to exogenous ligands, and that the C-terminal domain has a novel fold. Biosensor studies show that PCSK9 binds the extracellular domain of LDL receptor with K(d) = 170 nM at the neutral pH of plasma, but with a K(d) as low as 1 nM at the acidic pH of endosomes. The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH. PCSK9 may diminish LDL receptors by a mechanism that requires direct binding but not necessarily receptor proteolysis.

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Crossref · 10.1038/nsmb1235

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2 of 2 references verified0 citation errors · 0 not checkable

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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 [129]

  • The 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 [129]

  • PCSK9 is highly expressed in hepatocytes and is synthesized as a zymogen that undergoes autocatalytic processing in the endoplasmic reticulum.

    “PCSK9 is highly expressed in hepatocytes and is synthesized as a zymogen that undergoes autocatalytic processing in the endoplasmic reticulum.12,13”

    From Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation (2025) · cites this paper as [13]

Citations

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Research works printed but not linked: 31

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Metadata

Authors
Cunningham, D., Danley, D. E., Geoghegan, K. F., Griffor, M. C., Hawkins, J. L., Subashi, T. A., Varghese, A. H., Ammirati, M. J., Culp, J. S., Hoth, L. R., Mansour, M. N., McGrath, K. M., Seddon, A. P., Shenolikar, S., Stutzman-Engwall, K. J., Warren, L. C., Xia, D., & Qiu, X.
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2007-04-15
Volume
14
Issue
5
Pages
413-419
ISSN
  • 1545-9993
  • 1545-9985
DOI
10.1038/nsmb1235
Cited by
409
References
2
Language
en
Licence
www.springer.com/tdm (tdm)

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