Abstract
We previously isolated and sequenced the approximately 250-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 full-length 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.
Highlights
A new, highly conserved type 1 receptor, termed sorLA/ LR11, was recently identified in man, rodents, chicken, and hydra (1– 6)
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
We recently showed that sortilin-1 (ϳ95 kDa), whose lumenal part consists of a Vps10p domain only, is conditioned for binding of ligands such as receptor-associated protein (RAP), neurotensin, and lipoprotein lipase (LpL) by furin-mediated cleavage and removal of the propeptide (15, 17)
Summary
A new, highly conserved type 1 receptor, termed sorLA/ LR11, was recently identified in man, rodents, chicken, and hydra (1– 6). Concerning non-neuronal cells, recent results have shown low expression of sorLA in normal rabbit aortas but a comparatively marked expression in the intimal smooth muscle cells of aortas displaying atheromatous lesions in rabbits fed with a high cholesterol diet (12). These observations suggest that sorLA may play a role in developmental cellular proliferation and in pathological events. The head activator, a conserved 11-residue peptide of unknown function in mammals, stimulates head-specific growth in hydra and is reported to stimulate mitosis in NT2 cells (6, 16) These results, together with the structural features, suggest that sorLA is a multifunctional receptor that may be involved in ligand transport and sorting and perhaps in the propagation of ligand-induced signaling. It seemed possible that sorLA, like sortilin-1, is synthesized as a proreceptor and activated by truncation
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