Abstract
Nogo is a myelin-derived protein that limits axonal regeneration after CNS injury. A short hydrophilic Nogo-66 loop between two hydrophobic domains of Nogo binds to a Nogo-66 receptor (NgR) to inhibit axonal outgrowth. Inhibition of axon outgrowth and cell spreading by a second Nogo domain, termed Amino-Nogo-A, is thought to be mediated by a distinct receptor complex. Here, we define a novel Nogo-A-specific domain in Amino-Nogo that binds to NgR with nanomolar affinity. This second domain of 24 amino acids does not alter cell spreading or axonal outgrowth. Fusion of the two NgR-binding Nogo-A domains creates a ligand with substantially enhanced affinity for NgR and converts a NgR antagonist peptide to an agonist. Thus, NgR activation by Nogo-A involves multiple sites of interaction between Nogo-A and NgR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaline Phosphatase / genetics
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Animals
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Axons / physiology
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Binding Sites
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Cell Line
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Chick Embryo
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Chlorocebus aethiops
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GPI-Linked Proteins
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Glutathione Transferase / genetics
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Humans
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In Vitro Techniques
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Ligands
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Mice
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Myelin Proteins / agonists
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Myelin Proteins / antagonists & inhibitors*
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Myelin Proteins / chemistry
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Myelin Proteins / genetics
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Myelin Proteins / metabolism*
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Nogo Proteins
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Nogo Receptor 1
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Peptides / chemistry
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Peptides / pharmacology
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Protein Isoforms / agonists
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Protein Structure, Tertiary
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Receptors, Cell Surface / agonists
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Receptors, Cell Surface / antagonists & inhibitors*
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Receptors, Cell Surface / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism*
Substances
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GPI-Linked Proteins
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Ligands
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Myelin Proteins
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Nogo Proteins
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Nogo Receptor 1
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Peptides
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Protein Isoforms
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RTN4 protein, human
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Receptors, Cell Surface
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Recombinant Fusion Proteins
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Rtn4 protein, mouse
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Rtn4r protein, mouse
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Glutathione Transferase
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Alkaline Phosphatase