Identification of the amino acids on a neuronal glutamate receptor recognized by an autoantibody from a patient with paraneoplastic syndrome

Autoantibodies from a patient with paraneoplastic disease were identified p reviously to bind to the glutamate receptor (GluR) subunit GluR5 and to fun ction as potential allosteric modulators of receptor activity (Gahring et a l, [1995] Mol Med 1:245-253). In the present study we have used deletion ma pping and mutagenesis to define the residues in GluR5 bound by this autorea ctivity. The autoantibody contact residues include residues K497, N508, K51 0, E512, and to a lesser extent Q507, Residues 507-512 confer autoantibody specificity of the autoreactivity to GluR5. These residues have been shown in crystallographic studies (Armstrong et al, [1998] Nature 395: 913-917) t o participate in a loop structure, whereas residue K497 is located on a bet a-strand. Notably, this binding spans tyrosine 504, a residue important in forming the agonist-binding site. We propose that autoantibody binding of e ssential residues in this GluR5 autoantigenic region defines a subunit-spec ific allosteric regulatory site on neuronal glutamate receptors and suggest s how receptor dysfunction and region-specific neuronal death in the brain can progress in certain autoimmune neurological diseases. J, Neurosci. Res. 63. 480-485, 2001. (C) 2001 Wiley-Liss, Inc.