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The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH

Surdo, Paola Lo, Bottomley, Matthew J, Calzetta, Alessandra, Settembre, Ethan C, Cirillo, Agostino, Pandit, Shilpa, Ni, Yan G, Hubbard, Brian, Sitlani, Ayesha, Carfí, Andrea·2011·The EMBO Reports
DOI 10.1038/embor.2011.205
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Crossref · 10.1038/embor.2011.205

Cites

4 of 4 references verified0 citation errors · 0 not checkable

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  • Enhanced PCSK9 binding forces LDLR to remain in an open conformation, preventing its recycling and promoting degradation of LDLR.

    “This enhanced binding forces the LDLR to remain in an open conformation123,124, preventing its recycling and promoting degradation of LDLR.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [124]

    The Results and Discussion propose that PCSK9 might lock LDLR in an extended conformation and inhibit its transition to the closed form. Figure 4 describes how enhanced binding at endosomal pH could prevent changes associated with recycling and lead to LDLR degradation. The claim presents this proposed mechanism as an established effect by saying binding “forces” LDLR to remain open. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Pcsk9 targets Ldlr for lysosomal degradation rather than for recycling to the cell surface.

    “By binding to the EGF-A domain of Ldlr, Pcsk9 targets this receptor for lysosomal degradation rather than for recycling to the cell surface.20,21”

    From The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression (2015) · cites this paper as [20]

  • TMEM55B knockdown in human hepatoma cells reduced total LDLR protein level.

    “We found that TMEM55B knockdown in human hepatoma cells decreased intracellular cholesterol level, reduced total LDLR protein level, impaired LDL uptake, and increased LDLR protein degradation6.”

    From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [6]

    The Methods describe experiments on PCSK9 and LDLR proteins, and the Results and Discussion propose PCSK9-mediated LDLR downregulation; neither addresses TMEM55B knockdown in human hepatoma cells. Searches for TMEM55B knockdown and silencing found no passage reporting a change in total LDLR protein. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • TMEM55B knockdown in human hepatoma cells increased LDLR protein degradation.

    “We found that TMEM55B knockdown in human hepatoma cells decreased intracellular cholesterol level, reduced total LDLR protein level, impaired LDL uptake, and increased LDLR protein degradation6.”

    From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [6]

    The Methods describe experiments on PCSK9 and LDLR proteins, and the Results and Discussion propose a mechanism for PCSK9-mediated LDLR degradation. Searches for TMEM55B knockdown and hepatoma-cell LDLR degradation found no passage addressing the claimed experiment; the PCSK9 mechanism does not establish its result. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • TMEM55B knockdown in human hepatoma cells decreased intracellular cholesterol level.

    “We found that TMEM55B knockdown in human hepatoma cells decreased intracellular cholesterol level, reduced total LDLR protein level, impaired LDL uptake, and increased LDLR protein degradation6.”

    From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [6]

    The Methods describe experiments on PCSK9 and LDLR proteins, and the Results and Discussion address PCSK9-mediated LDLR downregulation. Searches for TMEM55B knockdown, hepatoma cells, and intracellular cholesterol found no passage in our copy reporting the claimed decrease. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 31

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  2. Arias‐Moreno X, Velazquez‐Campoy A, Rodriguez JC, Pocovi M, Sancho J (2008) Mechanism of low density lipoprotein (LDL) release in the endosome: implications of the stability and Ca2+ affinity of the fifth binding module of the LDL receptor. J Biol Chem 283: 22670–22679 · DOI
  3. Beglova N, Jeon H, Fisher C, Blacklow SC (2004) Cooperation between fixed and low pH‐inducible interfaces controls lipoprotein release by the LDL receptor. Mol Cell 16: 281–292 · DOI
  4. Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG (2006) The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post‐translational modifications. J Biol Chem 281: 30561–30572 · DOI · Paper page
  5. Bottomley MJ et al (2009) Structural and biochemical characterization of the wild type PCSK9‐EGF(AB) complex and natural familial hypercholesterolemia mutants. J Biol Chem 284: 1313–1323 · DOI
  6. Cunningham D et al (2007) Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol 14: 413–419 · DOI · Paper page
  7. Essalmani R, Susan‐Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, Seidah NG, Prat A (2011) In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem 286: 4257–4263 · DOI · Paper page
  8. Esser V, Limbird LE, Brown MS, Goldstein JL, Russell DW (1988) Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J Biol Chem 263: 13282–13290 · DOI · Paper page
  9. Fisher TS et al (2007) PCSK9‐dependent LDL receptor regulation: effects of pH and LDL. J Biol Chem 282: 20502–20512 · DOI · Paper page
  10. Goldstein JL, Basu SK, Brunschede GY, Brown MS (1976) Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans. Cell 7: 85–95 · DOI
  11. Hampton EN, Knuth MW, Li J, Harris JL, Lesley SA, Spraggon G (2007) The self‐inhibited structure of full‐length PCSK9 at 1.9 A reveals structural homology with resistin within the C‐terminal domain. Proc Natl Acad Sci USA 104: 14604–14609 · DOI
  12. Horton JD, Cohen JC, Hobbs HH (2009) PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 50 (Suppl): S172–S177 · DOI · Paper page
  13. Huang S, Henry L, Ho YK, Pownall HJ, Rudenko G (2010) Mechanism of LDL binding and release probed by structure‐based mutagenesis of the LDL receptor. J Lipid Res 51: 297–308 · DOI
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  15. Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC (2001) Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD‐EGF domain pair. Nat Struct Biol 8: 499–504 · DOI
  16. Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J (2008) Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci USA 105: 1820–1825 · DOI · Paper page
  17. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, Anderson NN, Ho YK, Hammer RE, Horton JD (2006) Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 116: 2995–3005 · DOI · Paper page
  18. Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE (2008) Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 72: 485–498 · DOI
  19. Mayer G, Poirier S, Seidah NG (2008) Annexin A2 is a C‐terminal PCSK9‐binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem 283: 31791–31801 · DOI · Paper page
  20. Mousavi SA, Berge KE, Berg T, Leren TP (2011) Affinity and kinetics of PCSK9 binding to LDL receptors on HepG2 cells. FEBS J 278: 2938–2950 · DOI · Paper page
  21. Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, McPherson PS, Attie AD, Prat A, Seidah NG (2007) The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic 8: 718–732 · DOI · Paper page
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Metadata

Authors
Surdo, P. L., Bottomley, M. J., Calzetta, A., Settembre, E. C., Cirillo, A., Pandit, S., Ni, Y. G., Hubbard, B., Sitlani, A., & Carfí, A.
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2011-11-11
Volume
12
Issue
12
Pages
1300-1305
ISSN
  • 1469-221X
  • 1469-3178
DOI
10.1038/embor.2011.205
Cited by
226
References
4
Language
en
Licence

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