Nueva estrategia para tratar el daño neuronal y las lesiones medulares

Heterodimerization of p45–p75 Modulates p75 Signaling: Structural Basis and Mechanism of Action

Abstract

The p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily, is required as a co-receptor for the Nogo receptor (NgR) to mediate the activity of myelin-associated inhibitors such as Nogo, MAG, and OMgp. p45/NRH2/PLAIDD is a p75 homologue and contains a death domain (DD). Here we report that p45 markedly interferes with the function of p75 as a co-receptor for NgR. P45 forms heterodimers with p75 and thereby blocks RhoA activation and inhibition of neurite outgrowth induced by myelin-associated inhibitors. p45 binds p75 through both its transmembrane (TM) domain and DD. To understand the underlying mechanisms, we have determined the three-dimensional NMR solution structure of the intracellular domain of p45 and characterized its interaction with p75. We have identified the residues involved in such interaction by NMR and co-immunoprecipitation. The DD of p45 binds the DD of p75 by electrostatic interactions. In addition, previous reports suggested that Cys257 in the p75 TM domain is required for signaling. We found that the interaction of the cysteine 58 of p45 with the cysteine 257 of p75 within the TM domain is necessary for p45–p75 heterodimerization. These results suggest a mechanism involving both the TM domain and the DD of p45 to regulate p75-mediated signaling.

Author Summary

Injuries to the brain and spinal cord often result in paralysis due to the fact that the injured nerves cannot regrow to reach their normal targets and carry out their functions. At the injury sites, there are proteins released from the damaged myelin that bind the Nogo receptor (NgR) on the nerve and inhibit its regeneration. The NgR needs to form a complex with the p75 neurotrophin receptor in order to mediate this inhibitory signal. Here we found that p45, a homologue of p75, can also bind to p75 and block its inhibitory activity when overexpressed. To perform its function, p75 needs to dimerize through both its transmembrane and intracellular domains, facilitating the recruitment of several proteins. Our structural and functional studies show that p45 binds specifically to conserved regions in the p75 transmembrane and the intracellular domain and that this blocks p75 dimerization along with its downstream signaling. Thus, this study demonstrates that altering the oligomerization of p75 is a good strategy to override p75's inhibitory effects on nerve regeneration, and it opens the door for the design of specific p75 inhibitors for therapeutic applications.