A model for a glutamate receptor agonist antibody-binding site.
A combination of mutagenesis, computer modeling and immunoreactivity has been used to develop a structural model of a segment of the glutamate receptor (GluR), termed GluR3B, which is bound by receptor-activating autoantibodies. In this model, the GluR3B epitope is located in a reverse hairpin loop that places key residues important for antibody recognition and receptor activation in a linear arrangement on the solvent-exposed surface. The conformation of the loop is stabilized by a hydrophobic core which is critical for functional integrity of the epitope. The proximity of the amino- and carboxy-terminal residues suggested that the GluR3B peptide could be cyclized without diminishing immunoreactivity through replacement of these residues with cysteines and formation of a disulfide bond. This prediction was confirmed experimentally since the cyclized peptide retained full immunoreactivity. The model provides insight into GluR subunit-specific functional diversity and the role of autoantibodies to this region in neurological disease.
McDonald
S
S
The Burnham Institute, La Jolla CA 92037, USA.
Carlson
N G
NG
Gahring
L C
LC
Ely
K R
KR
Rogers
S W
SW
D000595:Amino Acid Sequence; D000818:Animals; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D003553:Cystine / Q000737:chemistry; D000939:Epitopes / Q000276:immunology*; D018690:Excitatory Amino Acid Agonists / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018448:Models, Immunological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011817:Rabbits; D017470:Receptors, Glutamate / Q000737:chemistry / Q000276:immunology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D001323:Autoantibodies; D000939:Epitopes; D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; D003553:Cystine