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 ma...

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Bibliographic Details
Published in:Journal of neuroscience research 2001-03, Vol.63 (6), p.480-485
Main Authors: Carlson, Noel G., Gahring, Lorise C., Rogers, Scott W.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Autoantibodies - immunology
autoantibody
Autoantigens - genetics
Autoantigens - immunology
epitope
glutamate
Humans
Molecular Sequence Data
Mutagenesis - immunology
Nerve Degeneration - genetics
Nerve Degeneration - immunology
neurodegeneration
Paraneoplastic Syndromes - genetics
Paraneoplastic Syndromes - immunology
Protein Structure, Tertiary
receptor
Receptors, Kainic Acid - chemistry
Receptors, Kainic Acid - genetics
Receptors, Kainic Acid - immunology
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Summary: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. J. Neurosci. Res. 63:480–485, 2001. © 2001 Wiley‐Liss, Inc.
ISSN:0360-4012
1097-4547
DOI:10.1002/jnr.1042