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-Structure paper
タイトル | Structural mechanisms of GABA receptor autoimmune encephalitis. |
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ジャーナル・号・ページ | Cell, Vol. 185, Issue 14, Page 2469-2477.e13, Year 2022 |
掲載日 | 2022年7月7日 |
![]() | Colleen M Noviello / Jakob Kreye / Jinfeng Teng / Harald Prüss / Ryan E Hibbs / ![]() ![]() |
PubMed 要旨 | Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, ...Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABA) receptor. These antibodies induced severe encephalitis by directly inhibiting GABA function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABA inhibition and pathology. One antibody directly competes with a neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient. |
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手法 | EM (単粒子) |
解像度 | 3.0 Å |
構造データ | EMDB-25583, PDB-7t0w: EMDB-25585, PDB-7t0z: |
化合物 | ![]() ChemComp-ABU: ![]() ChemComp-NAG: ![]() ChemComp-MAN: |
由来 |
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![]() | MEMBRANE PROTEIN/IMMUNE SYSTEM / autoimmunity / encephalitis / GABA / inhibitory / MEMBRANE PROTEIN-IMMUNE SYSTEM complex |