Sortilin and sorCS1 [sortilin-related Vps10p (vacuolar protein sorting/targeting protein 10) domain-containing receptor 1], both members of the Vps10p-D (Vps10p-domain) receptor family, are synthesized as precursor proteins and are converted into their mature form by enzymatic cleavage of a short N-terminal propeptide. SorCS1 does not bind its propeptide, but sortilin is able to bind not just its own propeptide, but also that of sorCS1. In the present study we show that the propeptide region of sorCS1 contains two separate sites for binding to sortilin and that only one of these sites is removed from human (as opposed to mouse) sorCS1 during processing. This leaves mature human sorCS1 with a sortilin-binding N-terminus, which allows formation of a complex between the two receptors in solution and on cell membranes. Furthermore, we find that the interaction with sorCS1 has a pronounced effect on sortilin's ability to mediate the cellular uptake of alternative ligands, and to hamper its facilitation of CNTF (ciliary neutrophic factor) signalling and the induction of phosphorylated STAT3 (signal transducer and activator of transcription 3). Thus the present study reveals a novel regulatory mechanism and suggest an entirely new role for sorCS1 as a modulator of sortilin function.
- ciliary neutrophic factor (CNTF)
- α-galactosidase A
- sortilin-related Vps10p domain-containing receptor 1 (sorCS1)
- vacuolar protein sorting/targeting protein 10 (Vps10p)
Abbreviations: APP, amyloid precursor protein; cd, cytoplasmic domain; CHO-K1, Chinese-hamster ovary K1; CNTF, ciliary neutrophic factor; DMEM, Dulbecco’s modified Eagle’s medium; DSP, dithiobis(succinimidyl propionate); α-Gal A, α-galactosidase A; gp130, 130 kDa glycoprotein; HEK, human embryonic kidney; h-sorCS1, human sorCS1; h-sortilin, human sortilin; LIFR, leukaemia inhibitory factor receptor; m-sorCS1, mouse sorCS1; NT, neurotensin; PDGF-BB, platelet-derived growth factor-BB; PNGase-F, peptide N-glycosidase F; pSTAT3, phospho-STAT3; RAP, receptor-associated protein; sorCS, sortilin-related Vps10p-D-containing receptor; sorLA, sortilin-related receptor, L(DLR class) A repeats-containing; SPR, surface plasmon resonance; STAT3, signal transducer and activator of transcription 3; Vps10p, vacuolar protein sorting/targeting protein 10; Vps10p-D, Vps10p-domain; wt, wild-type
- © The Authors Journal compilation © 2014 Biochemical Society