Identification of a VLDL-induced, FDNPVY-independent internalization mechanism for the LDLR

Peter Michaely, Zhenze Zhao, Wei Ping Li, Rita Garuti, Lily J. Huang, Helen H. Hobbs, Jonathan C. Cohen

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The low-density lipoprotein (LDL) receptor (LDLR) binds to and internalizes lipoproteins that contain apolipoproteinB100 (apoB100) or apolipoproteinE (apoE). Internalization of the apoB100 lipoprotein ligand, LDL, requires the FDNPVY807 sequence on the LDLR cytoplasmic domain, which binds to the endocytic machinery of coated pits. We show here that inactivation of the FDNPVY807 sequence by mutation of Y807 to cysteine prevented the uptake of LDL; however, this mutation did not prevent LDLR-dependent uptake of the apoE lipoprotein ligand, β-VLDL. Comparison of the surface localization of the LDLR-Y807C using LDLR-immunogold, LDL-gold and β-VLDL-gold probes revealed enrichment of LDLR-Y807C-bound β-VLDL in coated pits, suggesting that β-VLDL binding promoted the internalization of the LDLR-Y807C. Consistent with this possibility, treatment with monensin, which traps internalized LDLR in endosomes, resulted in the loss of surface LDLR-Y807C only when β-VLDL was present. Reconstitution experiments in which LDLR variants were introduced into LDLR-deficient cells showed that the HIC818 sequence is involved in β-VLDL uptake by the LDLR-Y807C. Together, these experiments demonstrate that the LDLR has a very low-density lipoprotein (VLDL)-induced, FDNPVY-independent internalization mechanism.

Original languageEnglish (US)
Pages (from-to)3273-3282
Number of pages10
JournalEMBO Journal
Volume26
Issue number14
DOIs
StatePublished - Jul 25 2007

Keywords

  • ARH
  • Fibroblasts
  • LDL
  • LDLR
  • VLDL

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

Fingerprint

Dive into the research topics of 'Identification of a VLDL-induced, FDNPVY-independent internalization mechanism for the LDLR'. Together they form a unique fingerprint.

Cite this