Article
- The EMBO Journal (2007) 26, 3273 - 3282
- doi:10.1038/sj.emboj.7601769
Published online: 21 June 2007
Subject Categories:
Identification of a VLDL-induced, FDNPVY-independent internalization mechanism for the LDLR
Peter Michaely1, Zhenze Zhao1, Wei-Ping Li1, Rita Garuti2, Lily J Huang1, Helen H Hobbs2,3,4 and Jonathan C Cohen3,5
- Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX, USA
- McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX, USA
- Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, USA
Correspondence to:
Peter Michaely, Department of Cell Biology, The University of Texas Southwestern Medical Center, Room K2.235, 5323 Harry Hines Blvd., Dallas, TX 75390-9039, USA. Tel.: +1 214 648 3238; Fax: +1 214 648 8694; E-mail: peter.michaely@utsouthwestern.edu
Received 27 September 2006; Accepted 30 May 2007
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, 
-VLDL. Comparison of the surface localization of the LDLR-Y807C using LDLR-immunogold, LDL-gold and -VLDL-gold probes revealed enrichment of LDLR-Y807C-bound -VLDL in coated pits, suggesting that -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 -VLDL was present. Reconstitution experiments in which LDLR variants were introduced into LDLR-deficient cells showed that the HIC818 sequence is involved in -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.
Keywords:
- ARH,
- fibroblasts,
- LDL,
- LDLR,
- VLDL
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