Molecular Characterization of a Novel Human Hybrid-type Receptor That Binds the α2-Macroglobulin Receptor-associated Protein

doi:10.1074/jbc.271.49.31379

Molecular Characterization of a Novel Human Hybrid-type Receptor That Binds the α₂-Macroglobulin Receptor-associated Protein*

From the Department of ^‡ Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark and the
^¶ Department of Molecular and Structural Biology, University of Aarhus, DK-8000 Aarhus C, Denmark
^∥ Department of Medical Genetics, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark

^§ To whom correspondence should be addressed:
Dept. of Medical Biochemistry, University of Aarhus, Ole Worms Allé, Bldg. 170, DK-8000 Aarhus C, Denmark.
Tel: 45-89-422880; Fax: 45-86-131160.

Abstract

The 39-40-kDa receptor-associated protein (RAP) binds to the members of the low density lipoprotein receptor gene family and functions as a specialized endoplasmic reticulum/Golgi chaperone. Using RAP affinity chromatography, we have purified a novel ∼250-kDa brain protein and isolated the corresponding cDNA. The gene, designated SORL1, maps to chromosome 11q 23/24 and encodes a 2214-residue type 1 receptor containing a furin cleavage site immediately preceding the N terminus determined in the purified protein. The receptor, designated sorLA-1, has a short cytoplasmic tail containing a tyrosine-based internalization signal and a large external part containing (from the N-terminal): 1) a segment homologous to domains in the yeast vacuolar protein sorting 10 protein, Vps10p, that binds carboxypeptidase Y, 2) five tandemly arranged YWTD repeats and a cluster of 11 class A repeats characteristic of the low density lipoprotein receptor gene family receptors, and 3) six tandemly arranged fibronectin type III repeats also found in certain neural adhesion proteins. sorLA-1 may therefore be classified as a hybrid receptor. Northern blotting revealed specific mRNA transcripts in brain, spinal cord, and testis but not in several major organs. Both RAP and an antibody against a synthetic peptide derived from a sequence determined in the mature protein detected sorLA-1 in crude human brain extracts. The domain structure suggests that sorLA-1 is an endocytic receptor possibly implicated in the uptake of lipoproteins and of proteases.

Footnotes

↵* This work was supported by grants from The Danish Medical Research Council, The Danish Science Research Council, The Danish Biotechnology Program, The Danish Cancer Society, The Novo Nordic Foundation, and The Carlsberg Foundation. 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) U60975[GenBank].
↵¹ The abbreviations used are:

RAP

receptor-associated protein

sorLA-1

sorting protein-related receptor containing LDL receptor class A repeats

LDLR

low density lipoprotein receptor

LRP

LDL receptor-related protein/α₂-macroglobulin receptor

aa

amino acid(s)

kb

kilobase(s)

PAGE

polyacrylamide gel electrophoresis

CHAPS

3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid

FLpter

fractional length p-terminal.
↵² C.M. Petersen, M.S. Nielsen, A. Nykjær, L. Jacobsen, N. Tommerup, H. H. Rasmussen, H. Røigaard, J. Gliemann, P. Madsen, and S. K. Moestrup, submitted for publication.
- Received September 10, 1996.