The closed conformation of the LDL receptor is destabilized by the low Ca(++) concentration but favored by the high Mg(++) concentration in the endosome

FEBS Lett. 2015 Nov 30;589(23):3534-40. doi: 10.1016/j.febslet.2015.10.014. Epub 2015 Oct 23.

Abstract

The LDL receptor (LDLR) internalizes LDL and VLDL particles. In the endosomes, it adopts a closed conformation important for recycling, by interaction of two modules of the ligand binding domain (LR4-5) and a β-propeller motif. Here, we investigate by SPR the interactions between those two modules and the β-propeller. Our results indicate that the two modules cooperate to bind the β-propeller. The binding is favored by low pH and by high [Ca(++)]. Our data show that Mg(++), at high concentration in the endosome, favors the formation of the closed conformation by replacing the structuring effect of Ca(++) in LR5. We propose a sequential model of LDL release where formation of the close conformation follows LDL release.

Keywords: Binding; Endosome; Low density lipoprotein receptor; Surface plasmon resonance.

MeSH terms

  • Amino Acid Motifs / drug effects
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Endosomes / metabolism*
  • Epidermal Growth Factor / metabolism
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Lipoproteins / metabolism
  • Magnesium / metabolism*
  • Magnesium / pharmacology
  • Models, Molecular
  • Protein Stability / drug effects
  • Protein Structure, Tertiary / drug effects
  • Receptors, LDL / chemistry*
  • Receptors, LDL / metabolism*
  • Surface Plasmon Resonance

Substances

  • Lipoproteins
  • Receptors, LDL
  • Epidermal Growth Factor
  • Magnesium
  • Calcium