Nogo Receptor's Promiscuous Structure

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Multiple proteins that inhibit axon outgrowth bind to the glycophosphatidyl inositol-linked Nogo receptor (NgR), which signals by interaction with the neurotrophin p75 receptor (p75NTR). These include all three isoforms of Nogo (Nogo-A, Nogo-B, and Nogo-C), as well as such divergent proteins as myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp). The structures of these proteins are not conserved, with only a short 66-amino acid C-terminal region of the Nogos responsive for NgR binding, MAG containing five immunoglobulin(Ig)-like repeats, and OMgp containing a leucine-rich repeat (LRR) domain. To determine how these structurally variable ligands can all bind NgR with high affinity, He et al. crystallized the extracellular domain of NgR. The extracellular domain adopts a typical LRR structure and contains nine repeats with cysteine-rich "capping" modules at each end. LRRs are known for presenting surfaces for protein interaction and serving as scaffolding domains. Conservation analysis by alignment of NgR-like sequences from multiple species and analysis to map the evolutionary information onto the structure indicated that the concave side of the LRR was most conserved and thus the most likely to be involved in ligand binding. The structure was also analyzed for hallmarks of protein-protein interaction domains on the basis of surface analysis of structures in the Protein Data Bank, and three "hotspots" for protein interaction on the concave face were identified. At the C-terminal end of the structure on the convex side is another potential binding pocket, possibly for interaction with the p75NTR. The structural properties of the LRR may allow the structural flexibility necessary for recognition of highly divergent ligands. X. L. He, J. F. Bazan, G. McDermott, J. B. Park, K. Wang, M. Tessier-Lavigne, Z. He, K. C. Garcia, Structure of the Nogo receptor ectodomain: A recognition module implicated in myelin inhibition. Neuron 38 , 177-185 (2003). [Online Journal]