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- EMDB-25583: Complex of GABA-A synaptic receptor with autoimmune antibody Fab115 -

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Basic information

Entry
Database: EMDB / ID: EMD-25583
TitleComplex of GABA-A synaptic receptor with autoimmune antibody Fab115
Map data
Sample
  • Complex: Complex between autoantibody Fab115 and the a2b2g2 GABA-A receptor
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit beta-2
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit alpha-1
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit gamma-2
    • Protein or peptide: Fab115 light chain, IgG1
    • Protein or peptide: Fab115 Heavy Chain, IgG1
Keywordsautoimmunity / encephalitis / GABA / inhibitory / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


benzodiazepine receptor activity / GABA receptor complex / inner ear receptor cell development / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation ...benzodiazepine receptor activity / GABA receptor complex / inner ear receptor cell development / cellular response to histamine / GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / inhibitory synapse assembly / innervation / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / postsynaptic specialization membrane / neurotransmitter receptor activity / chloride channel activity / cochlea development / adult behavior / Signaling by ERBB4 / chloride channel complex / regulation of postsynaptic membrane potential / transmembrane transporter complex / GABA-ergic synapse / chloride transmembrane transport / dendrite membrane / post-embryonic development / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cytoplasmic vesicle membrane / chemical synaptic transmission / postsynaptic membrane / postsynapse / dendritic spine / neuron projection / axon / synapse / extracellular exosome / plasma membrane
Similarity search - Function
Gamma-aminobutyric-acid A receptor, gamma 2 subunit / Gamma-aminobutyric acid receptor subunit gamma-1/4 / Gamma-aminobutyric-acid A receptor, alpha 1 subunit / : / Gamma-aminobutyric-acid A receptor, beta subunit / Gamma-aminobutyric-acid A receptor, alpha subunit / : / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. ...Gamma-aminobutyric-acid A receptor, gamma 2 subunit / Gamma-aminobutyric acid receptor subunit gamma-1/4 / Gamma-aminobutyric-acid A receptor, alpha 1 subunit / : / Gamma-aminobutyric-acid A receptor, beta subunit / Gamma-aminobutyric-acid A receptor, alpha subunit / : / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
Gamma-aminobutyric acid receptor subunit alpha-1 / Gamma-aminobutyric acid receptor subunit gamma-2 / Gamma-aminobutyric acid receptor subunit beta-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsNoviello CM / Hibbs RE / Kreye J / Teng J / Pruss H
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) United States
CitationJournal: Cell / Year: 2022
Title: Structural mechanisms of GABA receptor autoimmune encephalitis.
Authors: Colleen M Noviello / Jakob Kreye / Jinfeng Teng / Harald Prüss / Ryan E Hibbs /
Abstract: 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.
History
DepositionNov 30, 2021-
Header (metadata) releaseJul 13, 2022-
Map releaseJul 13, 2022-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25583.png

Downloads & links

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Map

FileDownload / File: emd_25583.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 323.7 Å		1.08 Å/pix.
x 300 pix.
= 323.7 Å		1.08 Å/pix.
x 300 pix.
= 323.7 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.079 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.013
Minimum - Maximum-0.06429382 - 0.124552086
Average (Standard dev.)0.00022234274 (±0.0027605828)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 323.7 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_25583_additional_1.map
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Half map: #1

Fileemd_25583_half_map_1.map
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_25583_half_map_2.map
Projections & Slices
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Sample components

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Entire : Complex between autoantibody Fab115 and the a2b2g2 GABA-A receptor

EntireName: Complex between autoantibody Fab115 and the a2b2g2 GABA-A receptor
Components
  • Complex: Complex between autoantibody Fab115 and the a2b2g2 GABA-A receptor
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit beta-2
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit alpha-1
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit gamma-2
    • Protein or peptide: Fab115 light chain, IgG1
    • Protein or peptide: Fab115 Heavy Chain, IgG1

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Supramolecule #1: Complex between autoantibody Fab115 and the a2b2g2 GABA-A receptor

SupramoleculeName: Complex between autoantibody Fab115 and the a2b2g2 GABA-A receptor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gamma-aminobutyric acid receptor subunit beta-2

MacromoleculeName: Gamma-aminobutyric acid receptor subunit beta-2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.40759 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVNDPSNMS LVKETVDRLL KGYDIRLRPD FGGPPVAVGM NIDIASIDMV SEVNMDYTLT MYFQQAWRDK RLSYNVIPLN LTLDNRVAD QLWVPDTYFL NDKKSFVHGV TVKNRMIRLH PDGTVLYGLR ITTTAACMMD LRRYPLDEQN CTLEIESYGY T TDDIEFYW ...String:
QSVNDPSNMS LVKETVDRLL KGYDIRLRPD FGGPPVAVGM NIDIASIDMV SEVNMDYTLT MYFQQAWRDK RLSYNVIPLN LTLDNRVAD QLWVPDTYFL NDKKSFVHGV TVKNRMIRLH PDGTVLYGLR ITTTAACMMD LRRYPLDEQN CTLEIESYGY T TDDIEFYW RGDDNAVTGV TKIELPQFSI VDYKLITKKV VFSTGSYPRL SLSFKLKRNI GYFILQTYMP SILITILSWV SF WINYDAS AARVALGITT VLTMTTINTH LRETLPKIPY VKAIDMYLMG CFVFVFMALL EYALVNYIFF SQPARAAAID RWS RIFFPV VFSFFNIVYW LYYV

UniProtKB: Gamma-aminobutyric acid receptor subunit beta-2, Gamma-aminobutyric acid receptor subunit beta-2

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Macromolecule #2: Gamma-aminobutyric acid receptor subunit alpha-1

MacromoleculeName: Gamma-aminobutyric acid receptor subunit alpha-1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.831836 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QPSLQDELKD NTTVFTRILD RLLDGYDNRL RPGLGERVTE VKTDIFVTSF GPVSDHDMEY TIDVFFRQSW KDERLKFKGP MTVLRLNNL MASKIWTPDT FFHNGKKSVA HNMTMPNKLL RITEDGTLLY TMRLTVRAEC PMHLEDFPMD AHACPLKFGS Y AYTRAEVV ...String:
QPSLQDELKD NTTVFTRILD RLLDGYDNRL RPGLGERVTE VKTDIFVTSF GPVSDHDMEY TIDVFFRQSW KDERLKFKGP MTVLRLNNL MASKIWTPDT FFHNGKKSVA HNMTMPNKLL RITEDGTLLY TMRLTVRAEC PMHLEDFPMD AHACPLKFGS Y AYTRAEVV YEWTREPARS VVVAEDGSRL NQYDLLGQTV DSGIVQSSTG EYVVMTTHFH LKRKIGYFVI QTYLPCIMTV IL SQVSFWL NRESVPARTV FGVTTVLTMT TLSISARNSL PKVAYATAMD WFIAVCYAFV FSALIEFATV NYFTKSQPAR AAK IDRLSR IAFPLLFGIF NLVYWATYLN R

UniProtKB: Gamma-aminobutyric acid receptor subunit alpha-1, Gamma-aminobutyric acid receptor subunit alpha-1

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Macromolecule #3: Gamma-aminobutyric acid receptor subunit gamma-2

MacromoleculeName: Gamma-aminobutyric acid receptor subunit gamma-2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.35466 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: WSHPQFEKGG GSGGGSGGSS AWSHPQFEKL EVLFQGPQKS DDDYEDYASN KTWVLTPKVP EGDVTVILNN LLEGYDNKLR PDIGVKPTL IHTDMYVNSI GPVNAINMEY TIDIFFAQTW YDRRLKFNST IKVLRLNSNM VGKIWIPDTF FRNSKKADAH W ITTPNRML ...String:
WSHPQFEKGG GSGGGSGGSS AWSHPQFEKL EVLFQGPQKS DDDYEDYASN KTWVLTPKVP EGDVTVILNN LLEGYDNKLR PDIGVKPTL IHTDMYVNSI GPVNAINMEY TIDIFFAQTW YDRRLKFNST IKVLRLNSNM VGKIWIPDTF FRNSKKADAH W ITTPNRML RIWNDGRVLY TLRLTIDAEC QLQLHNFPMD EHSCPLEFSS YGYPREEIVY QWKRSSVEVG DTRSWRLYQF SF VGLRNTT EVVKTTSGDY VVMSVYFDLS RRMGYFTIQT YIPCTLIVVL SWVSFWINKD AVPARTSLGI TTVLTMTTLS TIA RKSLPK VSYVTAMDLF VSVCFIFVFS ALVEYGTLHY FVSSQPARAA KMDSYARIFF PTAFCLFNLV YWVSYLYL

UniProtKB: Gamma-aminobutyric acid receptor subunit gamma-2, Gamma-aminobutyric acid receptor subunit gamma-2

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Macromolecule #4: Fab115 light chain, IgG1

MacromoleculeName: Fab115 light chain, IgG1 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.838242 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNTVSWYQQL PGTAPKLLIY STNQRPSGVP DRFSGSKSGT SASLAIGGLQ SEDEADYYC AAWDDSLKRL VVFGGGTRLT VLGQPKAAPS VTLFPPSSEE LQANKATLVC LISDFYPGAV TVAWKADSSP V KAGVETTT ...String:
QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNTVSWYQQL PGTAPKLLIY STNQRPSGVP DRFSGSKSGT SASLAIGGLQ SEDEADYYC AAWDDSLKRL VVFGGGTRLT VLGQPKAAPS VTLFPPSSEE LQANKATLVC LISDFYPGAV TVAWKADSSP V KAGVETTT PSKQSNNKYA ASSYLSLTPE QWKSHRSYSC QVTHEGSTVE KTVAPTECS

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Macromolecule #5: Fab115 Heavy Chain, IgG1

MacromoleculeName: Fab115 Heavy Chain, IgG1 / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.625508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKASGYTFI SYDINWVRQA TGQGLEWMGG MDPKSGNTGY AQKFQGRVTM TTNTAISTAY MELSSLRSE DTAVYYCVRG EQSYDRTGYS DWFDPWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP E PVTVSWNS ...String:
QVQLVQSGAE VKKPGASVKV SCKASGYTFI SYDINWVRQA TGQGLEWMGG MDPKSGNTGY AQKFQGRVTM TTNTAISTAY MELSSLRSE DTAVYYCVRG EQSYDRTGYS DWFDPWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP E PVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHDYKDDD DK HHHHHH

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 788748
Initial angle assignmentType: OTHER / Software - Name: RELION (ver. 3.1) / Details: Initial Euler Angle Assignment
Final angle assignmentType: OTHER / Software - Name: RELION (ver. 3.1) / Details: Final Euler Angle Assignment

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