Protein Folding at the Membrane Interface: The Structure of Nogo-66

Abstract

Compelling evidence indicates that repair of damage to the central nervous system (CNS) is inhibited by the presence of protein factors within myelin that prevent axonal regrowth. Myelin growth inhibits and their common receptor have been identified as targets in the treatment of damage to the CNS.We have recently determined the NMR structure of one of the myelin growth inhibitors, the neurite outgrowth inhibitor (Nogo). We studied the structure of this protein alone and in the presence of dodecylphosphocholine micelles to mimic the natural cell membrane environment. Using several paramagnetic probes, we have defined portions of the growth inhibitor that are accessible to solvent (and consequently the Nogo receptor). Mutagenesis probed through phage-display confirms that the positions predicted to be extra-cellular are sensitive to receptor binding. Using computational docking methods and the mutagenesis results, we calculated the optimal protein-protein interface between our structure of Nogo and the Nogo receptor. The structure of Nogo and the predicted Nogo/receptor inhibitory complex structure will be presented.Funding was provided by: NIH 1R01GM078528-01 andCal Roman Reed Res Fund RR03-072, +114, +155