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Proteins. 2007 Jul 1;68(1):100-8.

The N- and C-termini of the human Nogo molecules are intrinsically unstructured: bioinformatics, CD, NMR characterization, and functional implications.

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  • 1Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.

Abstract

RTN4 or Nogo proteins are composed of three alternative splice forms, namely 1192-residue Nogo-A, 373-residue Nogo-B, and 199-residue Nogo-C. 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, and generation/maintenance of the tubular network of the endoplasmic reticulum (ER). Despite their significantly-different N-terminal lengths, they share a conserved C-terminal reticulon-homology domain consisting of two transmembrane fragments, a 66-residue extracellular loop Nogo-66 and a 38-residue C-tail carrying ER retention motif. Nogo-A owns the largest N-terminus with 1016 residues while the Nogo-B has an N-terminus almost identical to the first 200 residues of Nogo-A. So far, except for our previous determination of the Nogo-66 solution structure, no structural characterization of the other Nogo regions has been reported. In the present study, we initiated a systematically investigation of structural properties of Nogo molecules by a combined use of bioinformatics, CD, and NMR spectroscopy. The results led to two striking findings: (1) in agreement with bioinformatics prediction, the N- and C-termini of Nogo-B were experimentally demonstrated to be intrinsically unstructured by CD, two-dimensional 1H 15N NMR HSQC, hydrogen exchange, and 15N heteronuclear NOE characterization. (2) Further studies showed that the 1016-residue N-terminus of Nogo-A was again highly disordered. Therefore, it appears that being intrinsically-unstructured allows Nogo molecules to serve as double-faceted functional players, with one set of functions involved in cellular signaling processes essential for CNS neuronal regeneration, vascular remodeling, apoptosis and so forth and with another in generating/maintaining membrane-related structures. We propose that this mechanism may represent a general strategy to place the formation/maintenance of membrane-related structures under the direct regulation of the cellular signaling.

2007 Wiley-Liss, Inc.

PMID:
17397058
[PubMed - indexed for MEDLINE]
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