LDLR, pH, and Ca2+

The low-density lipoprotein receptor (LDLR) internalizes lipoproteins (LDL, VLDL) as part of a cycle between the cell surface and endosomes.

The cycle starts at the cell surface where the LDLR binds to lipoprotein.These LDLR-lipoprotein complexes are internalized through clathrin-coated pits into small endocytic vesicles.

These vesicles rapidly acidify and lose calcium, which together drives release of lipoprotein from the LDLR. The released lipoprotein remains in the endocytic vesicles, while the LDLR is trafficked back to the cell surface for further rounds of uptake.

Lipoprotein that is released in endocytic vesicles is trafficked to lysosomes where their cholesterol and fatty acid contents are liberated for use by the cell.

Work performed in our lab has shown how the LDLR responds to low pH and low calcium concentrations to release lipoprotein in endocytic vesicles.


  • Pompey SN, Michaely P, Luby-Phelps K. Quantitative Fluorescence Co-localization of Lipoproteins with the LDLR. Methods Mol Biol. 2013 1008:439-53. PMID: 23729262.
  • Pompey S, Zhao Z, Phelps K, Michaely P. Quantitative fluorescence imaging reveals point of release for lipoproteins during LDLR-dependent uptake. J Lipid Res. 2013 54:744-53. PMID: 23296879.
  • Zhao Z, Michaely P. Role of an intramolecular contact on lipoprotein uptake by the LDL receptor. Biochim Biophys Acta. 2011 1811:397-408 PMID: 21511053.
  • Zhao Z, Michaely P. The role of calcium in lipoprotein release by the low-density lipoprotein receptor. Biochemistry. 2009 48:7313-24. PMID: 19583244.
  • Zhao Z, Michaely P. The EGF-homology domain of the LDL receptor drives lipoprotein release through an allosteric mechanism involving H190, H562 and H586. J. Biol. Chem. 2008 283: 26528-37. PMID: 18677035.