Elements of Neural Adhesion Molecules and a Yeast Vacuolar Protein Sorting Receptor Are Present in a Novel Mammalian Low Density Lipoprotein Receptor Family Member

Hiroyuki Yamazaki,Hideaki Bujo,Jun Kusunoki,Kouichi Seimiya,Tatsuro Kanaki,Nobuhiro Morisaki,Wolfgang Johann Schneider,Yasushi Saito

doi:10.1074/jbc.271.40.24761

Abstract

Normal cell development depends to a large part on multifunctional proteins that have evolved by recombination of proven modular elements. We now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotein (LDL) receptor gene family. The extracellular portion of the approximately 250-kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor "YWTD" repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, in particular the hippocampus, dentate gyrus, and cerebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apolipoprotein E-containing lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The identification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunctional mosaic proteins akin to the ever expanding LDL receptor gene family.

Highlights

The discovery of the low density lipoprotein (LDL) receptor (LDLR)1 and its functional and genetic characterization were hallmarks in research on lipoprotein transport pathways and led to the molecular delin
A New Member of the LDLR Gene Family, LR11, Is a Type I Transmembrane Protein—Fig. 1 presents the amino acid sequence deduced from the rabbit LR11 cDNA obtained by homology cloning based on LDLR ligand binding repeat sequences
The LR11 Protein Contains Structural Modules of Several Proteins—The predicted amino acid sequence suggests that mature LR11 has seven distinct domains (Fig. 2), briefly described as: domain I, the NH2-terminal ϳ350 amino acids; domain II, a segment related to a yeast receptor for vacuolar protein sorting; domain III, five tandem LDLR “YWTD” repeats; domain IV, 11 LDLR ligand binding repeats; domain V, 6 motifs related to the fibronectin-type (FN) III repeat; domain VI, a putative membrane spanning region; and domain VII, at the COOH terminus, 54 amino acids predicted to be a cytoplasmic region with an internalization signal

Summary

Introduction

The discovery of the LDL receptor (LDLR)1 and its functional and genetic characterization were hallmarks in research on lipoprotein transport pathways and led to the molecular delin-. A New Member of the LDLR Gene Family, LR11, Is a Type I Transmembrane Protein—Fig. 1 presents the amino acid sequence deduced from the rabbit LR11 cDNA obtained by homology cloning based on LDLR ligand binding repeat sequences.

Results

Conclusion