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 previously to bind to the glutamate receptor (GluR) subunit GluR5 and to function as potential allosteric modulators of receptor activity (Gahring et al. [1995] Mol Med 1:245-253). In the present study we have used deletion mapping and mutagenesis to define the residues in GluR5 bound by this autoreactivity. The autoantibody contact residues include residues K497, N508, K510, 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) to participate in a loop structure, whereas residue K497 is located on a beta-strand. Notably, this binding spans tyrosine 504, a residue important in forming the agonist-binding site. We propose that autoantibody binding of essential residues in this GluR5 autoantigenic region defines a subunit-specific allosteric regulatory site on neuronal glutamate receptors and suggests how receptor dysfunction and region-specific neuronal death in the brain can progress in certain autoimmune neurological diseases.
Salt Lake City VA-Geriatrics Research, Education and Clinical Center, and University of Utah Medical Center, Salt Lake City 84112-5330, USA .
N G
NG
Carlson
L C
LC
Gahring
S W
SW
Rogers
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000276:immunology; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology; D010257:Paraneoplastic Syndromes / Q000235:genetics* / Q000276:immunology*; D017434:Protein Structure, Tertiary; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D018092:Kainic Acid Receptors