Recently RTN4/Nogo proteins have received intense attentions because they have been implicated in a variety of critical cellular processes including CNS neuronal regeneration, vascular remodeling, apoptosis, interaction with beta-amyloid protein converting enzyme (BACE) and formation/maintenance of the tubular network of the endoplamic reticulum (ER). Therefore, several years ago we initiated a systematic NMR characterization of Nogo proteins. Firstly, the successful determination of the solution structure of the buffer-insoluble Nogo-60 offered us rationales to successfully design structured and buffer-soluble Nogo-54, which can be used as a template to further design novel NgR antagonists to enhance CNS neuronal regeneration. Secondly, bioinformatics, CD and NMR characterization revealed that except for the Nogo66 loop, both N- and C-termini of Nogos were intrinsically-unstructured. We speculate that being intrinsically unstructured may allows Nogos to serve as double-faceted functional players, with one set of functions involved in cellular signaling processes and with another in forming/maintaining membrane-related structures. Integration of the two sets of functions in one intrinsically-unstructured protein may represent a general mechanism to place membrane-associated machineries under direct control by cellular signing.