Discovered as the molecules that block axon regeneration following injury, Nogo proteins are one of the most potent neurite growth inhibitors in the CNS. Nogo proteins function as negative regulators during development and serve as stabilizers of neuronal wiring in adult brain. A member of the Reticulon (RTN) family, alternative splicing and differential promoter usage results in the generation of three protein products (Nogo-A, -B, and -C) from a single gene (RTN4/NOGO).
The inhibitory actions of Nogo-A are dependent on two domains, Nogo-66 which is present in all three isoforms, and a sequence referred to as Nogo-delta 20, that is unique to the long N-terminal domain of Nogo-A. Nogo-A exerts its effects by binding to Nogo Receptor 1 (NgR1), via the Nogo-66 domain. Because NgR1 is glycosyl phosphatidylinositol (GPI)-linked to the plasma membrane, signal transduction requires the formation of a tripartite receptor complex that includes neurotrophin receptor p75 (NGF R) and the leucine-rich repeat and Ig domain containing Nogo receptor-interacting protein-1 (LINGO-1). When localized to the plasma membrane, LINGO-1 can be replaced as the signal transducer by TROY, an orphan receptor of the TNF receptor superfamily. Further studies suggest that Nogo-66 binds to Paired-Ig-like Receptor B (PIR-B).