Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography.
Receptor-associated protein (RAP) is an endoplasmic reticulum/Golgi protein involved in the processing of receptors of the low density lipoprotein receptor family. A approximately 95-kDa membrane glycoprotein, designated gp95/sortilin, was purified from human brain extracts by RAP affinity chromatography and cloned in a human cDNA library. The gene maps to chromosome 1p and encodes an 833-amino acid type I receptor containing an N-terminal furin cleavage site immediately preceding the N terminus determined in the purified protein. Gp95/sortilin is expressed in several tissues including brain, spinal cord, and testis. Gp95/sortilin is not related to the low density lipoprotein receptor family but shows intriguing homologies to established sorting receptors: a 140-amino acid lumenal segment of sortilin representing a hitherto unrecognized type of extracellular module shows extensive homology to corresponding segments in each of the two lumenal domains of yeast Vps10p, and the extreme C terminus of the cytoplasmic tail of sortilin contains the casein kinase phosphorylation consensus site and an adjacent dileucine sorting motif that mediate assembly protein-1 binding and lysosomal sorting of the mannose-6-phosphate receptors. Expression of a chimeric receptor containing the cytoplasmic tail of gp95/sortilin demonstrates evidence that the tail conveys colocalization with the cation-independent mannose6-phosphate receptor in endosomes and the Golgi compartment.
Petersen
C M
CM
Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark.
Nielsen
M S
MS
Nykjaer
A
A
Jacobsen
L
L
Tommerup
N
N
Rasmussen
H H
HH
Roigaard
H
H
Gliemann
J
J
Madsen
P
P
Moestrup
S K
SK
D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001923:Brain Chemistry; D002846:Chromatography, Affinity; D018076:DNA, Complementary / Q000737:chemistry; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000099183:Sortilin