Sortilin is a membrane protein that acts as co-receptor for p75NTR. Superior cervical ganglion (SCG) neurons, vascular smooth muscle (SM-11) cells, oligodendrocytes and CNS neurons (including basal forebrain neurons) (Volosin et al, 2006) express significant levels of sortilin and p75NTR. Schwann cells, instead, do not express sortilin. It is expressed during embryogenesis in areas where NGF and proNGF have well-characterized effects. It is important for proNGF signalling, but has little or no role on mature NGF initiated signalling. ProNGF preferentially binds to a p75NTR:sortilin complex, whereas mature NGF preferentially binds p75NTR alone. ProNGF binds to p75NTR with a dissociation constant (Kd) ~15-20 nM, and to sortilin with a Kd ~5 nM. In the presence of sortilin, proNGF binds to p75NTR with a Kd 0.2 nM. In contrast, mature NGF binds to p75NTR with a Kd of 1-2 nM, whereas it binds sortilin very weakly (Kd ~ 90 nM). Therefore, in the presence of sortilin, p75NTR binds more strongly to proNGF than to NGF, and proNGF signalling predominates. In the absence of sortilin, NGF binding is stronger than proNGF, and it is the mature NGF signalling that prevails. proNGF interacts with sortilin via its pro-domain, whereas the interaction with p75NTR is mediated by the mature domain.
Kliemannel, M, Lee, R, Jacobsen, C, Jansen, P, Teng, KK, Schwarz, E, Nykjaer, A, Nielsen, MS, Madsen, P, Petersen, CM, Hempstead, BL, Willnow, TE
Teng, KK, Lee, R, Kermani, P, Hempstead, BL
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