7t0w
From Proteopedia
(Difference between revisions)
| Line 14: | Line 14: | ||
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 gamma-aminobutyric acid type A (GABA(A)) receptor. These antibodies induced severe encephalitis by directly inhibiting GABA(A) function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABA(A) 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. | 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 gamma-aminobutyric acid type A (GABA(A)) receptor. These antibodies induced severe encephalitis by directly inhibiting GABA(A) function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABA(A) 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. | ||
| - | + | , PMID:35803245<ref>PMID:35803245</ref> | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Complex of GABA-A synaptic receptor with autoimmune antibody Fab115
| |||||||||||
Categories: Homo sapiens | Large Structures | Hibbs RE | Kreye J | Noviello CM | Pruss H | Teng J
