MOLECULAR CHARACTERIZATION OF A NOVEL HUMAN HYBRID-TYPE RECEPTOR THATBINDS THE ALPHA(2)-MACROGLOBULIN RECEPTOR-ASSOCIATED PROTEIN

The 39-40-kDa receptor-associated protein (RAP) binds to the members o f 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 similar to 250-kDa brain prot ein and isolated the corresponding cDNA. The gene, designated SORL1, m aps 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 internalizat ion signal and a large external part containing (from the N-terminal): 1) a segment homologous to domains in the yeast vacuolar protein sort ing 10 protein, Vps10p, that binds carboxypeptidase Y, 2) five tandeml y arranged YWTD repeats and a cluster of 11 class A repeats characteri stic of the low density lipoprotein receptor gene family receptors, an d 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 transcr ipts 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 hu man brain extracts. The domain structure suggests that sorLA-1 is an e ndocytic receptor possibly implicated in the uptake of lipoproteins an d of proteases.