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TitleStructural mechanisms of GABA receptor autoimmune encephalitis.
Journal, issue, pagesCell, Vol. 185, Issue 14, Page 2469-2477.e13, Year 2022
Publish dateJul 7, 2022
AuthorsColleen M Noviello / Jakob Kreye / Jinfeng Teng / Harald Prüss / Ryan E Hibbs /
PubMed AbstractAutoantibodies 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.
External linksCell / PubMed:35803245 / PubMed Central
MethodsEM (single particle)
Resolution3.0 Å
Structure data

25583

7t0w

EMDB-25583, PDB-7t0w:
Complex of GABA-A synaptic receptor with autoimmune antibody Fab115
Method: EM (single particle) / Resolution: 3.0 Å

25585

7t0z

EMDB-25585, PDB-7t0z:
Complex of GABA-A synaptic receptor with autoimmune antibody Fab175
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MAN:
alpha-D-mannopyranose

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / autoimmunity / encephalitis / GABA / inhibitory / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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