Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist.
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.
Hu
Fenghua
F
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Liu
Betty P
BP
Budel
Stephane
S
Liao
Ji
J
Chin
Joanna
J
Fournier
Alyson
A
Strittmatter
Stephen M
SM
D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D001369:Axons / Q000502:physiology; D001665:Binding Sites; D002460:Cell Line; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D058851:GPI-Linked Proteins; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D009185:Myelin Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*
D058851:GPI-Linked Proteins; D008024:Ligands; D009185:Myelin Proteins; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D010455:Peptides; D020033:Protein Isoforms; C000603199:RTN4 protein, human; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C000603201:Rtn4 protein, mouse; C419790:Rtn4r protein, mouse; D005982:Glutathione Transferase; D000469:Alkaline Phosphatase