Activation and Functional Characterization of the Mosaic Receptor SorLA/LR11

Abstract

We previously isolated and sequenced the ϳ250-kDa type 1 receptor sorLA/LR11, a mosaic protein with elements characterizing the Vps10p domain receptor family as well as the low density lipoprotein receptor family. The N terminus of the Vps10p domain comprises a consensus sequence for cleavage by furin ( 50 RRKR 53 ) that precedes a truncation found in sorLA isolated from human brain. Here we show that sorLA, like sortilin-1/ neurotensin receptor-3, whose lumenal domain consists of a Vps10p domain only, is synthesized as a proreceptor that is cleaved by furin in late Golgi compartments. We show that the truncation conditions the Vps10p domain for propeptide inhibitable binding of neuropeptides and the receptor-associated protein. We further demonstrate that avid binding of the receptor-associated protein, apolipoprotein E, and lipoprotein lipase not inhibited by propeptide occurs to sites located in other lumenal domains. In transfected cells, about 10% of fulllength sorLA were expressed on the cell surface capable of mediating endocytosis. However, the major pool of receptors was found in late Golgi compartments, suggesting possible interaction with newly synthesized ligands. The results show that sorLA, following activation by truncation, binds multiple ligands and may mediate both endocytosis and sorting.

Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme

“…These results raised the question of whether sorLA could mediate the internalization of cell surface APP and thereby also reduce the processing of APP into sAPP and A␤. It has been shown that sorLA is capable of mediating endocytosis (Jacobsen et al, 2001) and binds apolipoprotein E-rich lipoproteins and mediate their uptake (Taira et al, 2001). When we investigated uptake of APP from the cell surface, however, we found that APP internalization is independent of sorLA.…”

“…sorLA is a member of a novel family of vacuolar protein sorting 10 protein (Vps10p) receptors, which contain a domain with high homology to the yeast-sorting protein Vps10p (Yamazaki et al, 1996;Jacobsen et al, 2001). The 54-residue cytoplasmatic domain is highly similar to that of the cation-independent mannose 6-phosphate receptor and is also capable of binding Golgi apparatus-localized ␥-ear-containing ARF-binding (GGA) proteins (Jacobsen et al, 2002).…”

Sorting Protein-related Receptor SorLA Controls Regulated Secretion of Glial Cell Line-derived Neurotrophic Factor

“…Role of SorLA in Regulating GDNF Secretion-Considerable evidence supports that SorLA has multifunctional roles in Golgi-endosomal transport (21,24,33). The interaction of SorLA with GDNF, the localization of SorLA to GDNF-containing vesicles, and the assemblage in Golgi of both proteins prompts the hypothesis that SorLA might regulate the secretion of GDNF.…”

“…It is a member of a family of five mammalian proteins that share structural similarity with the vacuolar protein-sorting 10 protein (Vps10p), a sorting receptor in yeast that transports carboxypeptidase Y from the Golgi to the vacuole (23). The major pool of SorLA was found in late Golgi compartments, suggesting mediating transGolgi network-to-endosome sorting of newly synthesized ligands (24). SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (25)(26)(27).…”

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…The remaining binding sites were blocked by passage of 1 M ethanolamine, pH 8.5. The fulllength SorLA receptor was purified as described previously (34) and attached to the biosensor surface after dilution in sodium acetate buffer, pH 4.0, by standard procedures as described above.…”