Role of an intramolecular contact on lipoprotein uptake by the LDL receptor

Zhenze Zhao, Peter Michaely

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The LDL receptor (LDLR) is an endocytic receptor that plays a major role in the clearance of atherogenic lipoproteins from the circulation. During the endocytic process, the LDLR first binds lipoprotein at the cell surface and then traffics to endosomes, where the receptor releases bound lipoprotein. Release is acid-dependent and correlates with the formation of an intramolecular contact within the receptor. Human mutations at residues that form the contact are associated with familial hypercholesterolemia (FH) and the goal of the present study was to determine the role of contact residues on LDLR function. We show that mutations at nine contact residues reduce the ability of the LDLR to support lipoprotein uptake. Unexpectedly, only four of the mutations (W515A, W541A, H562Y and H586Y) impaired acid-dependent lipoprotein release. The remaining mutations decreased the lipoprotein-binding capacity of the LDLR through either reduction in the number of surface receptors (H190Y, K560W, H562Y and K582W) or reduction in the fraction of surface receptors that were competent to bind lipoprotein (W144A and W193A). We also examined three residues, distal to the contact, which were predicted to be necessary for the LDLR to adopt the acidic conformation. Of the three mutations we tested (G293S, F362A and G375S), one mutation (F362A) reduced lipoprotein uptake. Together, these data suggest that the intramolecular interface plays multiple roles in LDLR function.

Original languageEnglish (US)
Pages (from-to)397-408
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1811
Issue number6
DOIs
StatePublished - Jun 1 2011

Keywords

  • LDL
  • LDL receptor
  • LDLR
  • VLDL

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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