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

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 ϳ250-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.The 39 -40-kDa receptor associated protein (RAP) 1 binds to the members of the low density lipoprotein receptor (LDLR) gene family (1-4) and to the recently discovered human receptor gp95/sortilin.2 RAP is located predominantly in the endoplasmic reticulum and Golgi compartments and is thought to prevent aggregation and premature binding of ligands to the multifunctional LDLR family receptors (5, 6).In mammals, the known members of the LDLR family comprise LDLR itself, the very low density lipoprotein receptor, the apolipoprotein receptor 2, and the giant (ϳ600 kDa) multifunctional ␣ 2 -macroglobulin receptor/LDL receptor-related protein (LRP) and megalin. In addition, several related receptors have been discovered in chicken (7,8). The LDLR family members are type 1 receptors with short cytoplasmic tails containing one or a few FXNPXY internalization motifs. The extracellular domains contain 1) clusters of the ϳ40-residue LDLR class A repeats that display negatively charged surfaces stabilized by three disulfide bonds and bind ligands, including RAP (9, 10), 2) clusters of "spacer" regions containing the consensus peptide YWTD, and 3) single elements or pairs of growth factor repeats. In addition to the LDLR family members, a hybrid receptor with an N-terminal cluster of LDLR class A repeats and a C-terminal part similar to regions in guanine nucleotide binding protein-coupled receptors has been described in the mollusc Lymnea stagnalis (11). The RAP binding human gp95/sortilin is a type 1 recep...

Gene expression during testis development in Duroc boars

“…Expression of HSA sortilin (SORL1) was higher than in the reference sample in week 12 and 16, decreasing in week 20 and 27. This supports the suggestion that there is a higher level of endocytic activity at this age, as put forward by Jacobsen et al (1996). In addition, expression of EPS15 was higher than the reference value in week 12 (decreasing in weeks 16 to 27).…”

BCR/ABL-mediated downregulation of genes implicated in cell adhesion and motility leads to impaired migration toward CCR7 ligands CCL19 and CCL21 in primary BCR/ABL-positive cells

“…60 A possible role in leukemia or hematopoiesis has not been identified for the last three genes suppressed as a result of expression of BCR/ABL, namely SORL1, MX1, and BIRC1.The structure of the sorLa-1 protein encoded by SORL1 suggests that this is an endocytic receptor possibly implicated in uptake of lipoproteins and proteases. 61 Whether this protein is important in hematopoiesis has not been addressed. The protein encoded by the BIRC1 gene contains regions of homology to two baculovirus inhibitors of apoptosis, and suppresses apoptosis induced by various signals.…”

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

“…These studies led to the cloning of two type-1 transmembrane proteins termed sortilin 4 and sortilin-related receptor with A-type repeats (SORLA, also known as LR11) 5,6 . Although SORLA and sortilin bound apolipoproteins, they did not share much structural similarity to prototypical lipoprotein receptors of the LDLR gene family (Fig.…”