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

doi:10.1074/jbc.271.40.24761

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

From the ^‡ Second Department of Internal Medicine, Chiba University School of Medicine, Chiba 260, Japan, the
^§ Kowa Research Institute, Kowa Co. Ltd., Higashimurayama 189, Japan, and the
^¶ Department of Molecular Genetics, Biocenter and University of Vienna, A-1030 Vienna, Austria

^∥ Supported in part by a Lise-Meitner Postdoctoral Fellowship (M-004) from the Austrian Science Foundation. To whom correspondence should be addressed:
Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan
. Tel.: 81-43-222-7171 (ext. 5257); Fax: 81-43-226-2095.

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 ~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.

Footnotes

↵* This work was supported in part by a grant from the Japanese Ministry of Education, Science, and Culture (to Y. S.) and Austrian Science Foundation Grant F-0608 (to W. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) D86350[GenBank].
↵¹ The abbreviations used are:

LDLR

low density lipoprotein receptor

LR11

LDLR relative with 11 binding repeats

LR8(B)

LDLR relative with eight binding repeats (B)

apo

apolipoprotein

bp

base pair(s)

β-VLDL

β-migrating very low density lipoprotein

LRP

LDLR related protein/α₂-macroglobin receptor

EGF

epidermal growth factor

CHO

Chinese hamster ovary

PAGE

polyacrylamide gel electrophoresis

WHHL

Watanabe heritable hyperlipidemic

FNIII

fibronectin type III.
↵² S. Mörwald, H. Yamazaki, H. Bujo, J. Kusunoki, T. Kanaki, K. Seimiya, N. Morisaki, J. Nimpf, W. J. Schneider, and Y. Saito, manuscript in preparation.
- Received May 7, 1996.
- Revision received June 24, 1996.