Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein.
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 approximately 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.
Jacobsen
L
L
Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark.
Madsen
P
P
Moestrup
S K
SK
Lund
A H
AH
Tommerup
N
N
Nykjaer
A
A
Sottrup-Jensen
L
L
Gliemann
J
J
Petersen
C M
CM
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D017173:Caenorhabditis elegans; D002352:Carrier Proteins / Q000378:metabolism*; D002874:Chromosome Mapping; D018076:DNA, Complementary / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D006023:Glycoproteins / Q000378:metabolism*; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein; D026502:LDL-Receptor Related Proteins; D008562:Membrane Glycoproteins / Q000737:chemistry; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry; D014018:Tissue Distribution
D002352:Carrier Proteins; D018076:DNA, Complementary; D006023:Glycoproteins; D026541:Heymann Nephritis Antigenic Complex; D026563:LDL-Receptor Related Protein-Associated Protein; D026502:LDL-Receptor Related Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491167:Sorl1 protein, rat