Abstract
Author SummaryInjuries 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.
Highlights
The neurotrophin receptor p75 is a member of the tumor necrosis factor receptor (TNFR) superfamily and has four extracellular cysteine rich domains, a single transmembrane (TM) domain, and an intracellular domain (ICD) comprising a juxtamembrane and a death domain (DD) [1,2,3,4,5]
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
Summary
The neurotrophin receptor p75 is a member of the tumor necrosis factor receptor (TNFR) superfamily and has four extracellular cysteine rich domains, a single transmembrane (TM) domain, and an intracellular domain (ICD) comprising a juxtamembrane and a death domain (DD) [1,2,3,4,5]. Depending on co-receptor partners and cellular contexts, p75 may play seemingly opposing effects in multiple systems. P75 interacts with Trk receptors to promote neurotrophin-dependent nerve growth. P75 inhibits nerve growth mediated by myelin-associated inhibitors via functioning in part as a co-receptor for the GPI-linked neuronal Nogo-66 receptor (NgR) [6] or another non-NgR molecule that is yet to be identified [7,8]. Elucidation of the mechanisms that modulate p75-mediated signaling may increase our understanding of neural development and nerve injury
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