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- EMDB-62659: Cryo-EM structure of the LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex -

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Basic information

Entry
Database: EMDB / ID: EMD-62659
TitleCryo-EM structure of the LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex
Map data
Sample
  • Complex: The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 22
    • Protein or peptide: Leucine-rich glioma-inactivated protein 1
  • Ligand: CALCIUM ION
Keywordsepilepsy / synapse / adam / eptp / ed40 / cell adhesion
Function / homology
Function and homology information


LGI-ADAM interactions / axon initial segment / negative regulation of cell adhesion / neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of synaptic transmission / synaptic cleft / axon guidance / central nervous system development / postsynaptic density membrane / metalloendopeptidase activity ...LGI-ADAM interactions / axon initial segment / negative regulation of cell adhesion / neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of synaptic transmission / synaptic cleft / axon guidance / central nervous system development / postsynaptic density membrane / metalloendopeptidase activity / neuron projection development / integrin binding / nervous system development / positive regulation of cell growth / cell adhesion / axon / signaling receptor binding / dendrite / glutamatergic synapse / endoplasmic reticulum / Golgi apparatus / proteolysis / extracellular space / extracellular region / membrane / plasma membrane / cytoplasm
Similarity search - Function
Leucine-rich glioma-inactivated , EPTP repeat / EAR / : / EPTP domain / EAR repeat profile. / ADAM cysteine-rich / ADAM, cysteine-rich domain / ADAM Cysteine-Rich Domain / Disintegrin, conserved site / Disintegrins signature. ...Leucine-rich glioma-inactivated , EPTP repeat / EAR / : / EPTP domain / EAR repeat profile. / ADAM cysteine-rich / ADAM, cysteine-rich domain / ADAM Cysteine-Rich Domain / Disintegrin, conserved site / Disintegrins signature. / Peptidase M12B, propeptide / Reprolysin family propeptide / Reprolysin domain, adamalysin-type / Reprolysin (M12B) family zinc metalloprotease / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / EGF-like domain, extracellular / EGF-like domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Metallopeptidase, catalytic domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / EGF-like domain signature 1. / EGF-like domain / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Leucine-rich glioma-inactivated protein 1 / Disintegrin and metalloproteinase domain-containing protein 22
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsYamaguchi T / Okatsu K / Kubota M / Mitsumori A / Yamagata A / Fukai S
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
Citation
Journal: Elife / Year: 2025
Title: Structural insights into heterohexameric assembly of epilepsy-related ligand-receptor complex LGI1-ADAM22.
Authors: Takayuki Yamaguchi / Kei Okatsu / Masato Kubota / Ayuka Mitsumori / Atsushi Yamagata / Yuko Fukata / Masaki Fukata / Mikihiro Shibata / Shuya Fukai /
Abstract: Leucine-rich glioma-inactivated 1 protein (LGI1) is a secreted neuronal protein consisting of the N-terminal leucine-rich repeat (LRR) and C-terminal epitempin-repeat (EPTP) domains. LGI1 is linked ...Leucine-rich glioma-inactivated 1 protein (LGI1) is a secreted neuronal protein consisting of the N-terminal leucine-rich repeat (LRR) and C-terminal epitempin-repeat (EPTP) domains. LGI1 is linked to epilepsy, a neurological disorder that can be caused by genetic mutations of genes regulating neuronal excitability (e.g. voltage- or ligand-gated ion channels). ADAM22 is a membrane receptor that binds to LGI1 extracellularly and interacts with AMPA-type glutamate receptors via PSD-95 intracellularly to maintain normal synaptic signal transmission. Structural analysis of the LGI1-ADAM22 complex is important for understanding the molecular mechanism of epileptogenesis and developing new therapies against epilepsy. We previously reported the crystal structure of a 2:2 complex consisting of two molecules of LGI1 and two molecules of the ADAM22 ectodomain (ECD), which is suggested to bridge neurons across the synaptic cleft. On the other hand, multiangle light scattering, small-angle X-ray scattering, and cryo-electron microscopy (cryo-EM) analyses have suggested the existence of a 3:3 complex consisting of three molecules of LGI1 and three molecules of ADAM22. In the previous cryo-EM analysis, many observed particles were in a dissociated state, making it difficult to determine the three-dimensional (3D) structure of the 3:3 complex. In this study, we stabilized the 3:3 LGI1-ADAM22 complex using chemical cross-linking and determined the cryo-EM structures of the LGI1-LGI1-ADAM22 and 3:3 LGI1-ADAM22 complexes at 2.78 Å and 3.79 Å resolutions, respectively. Furthermore, high-speed atomic force microscopy (HS-AFM) visualized the structural features and flexibility of the 3:3 LGI1-ADAM22 complex in solution. We discuss new insights into the interaction modes of the LGI1-ADAM22 higher-order complex and the structural properties of the 3:3 LGI1-ADAM22 complex.
#1: Journal: Elife / Year: 2025
Title: Structural insights into heterohexameric assembly of epilepsy-related ligand-receptor complex LGI1-ADAM22.
Authors: Yamagachi T / Okatsu K / Kubota M / Mitsumori A / Yamagata A / Fukata Y / Fukata M / Shibata M / Fukai S
History
DepositionDec 10, 2024-
Header (metadata) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62659.png

Downloads & links

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Map

FileDownload / File: emd_62659.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 256 pix.
= 192.512 Å		0.75 Å/pix.
x 256 pix.
= 192.512 Å		0.75 Å/pix.
x 256 pix.
= 192.512 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.752 Å
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Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-1.6526622 - 2.3346868
Average (Standard dev.)-0.00004813024 (±0.05799122)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 192.512 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_62659_msk_1.map
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Additional map: #1

Fileemd_62659_additional_1.map
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Half map: #2

Fileemd_62659_half_map_1.map
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Half map: #1

Fileemd_62659_half_map_2.map
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Sample components

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Entire : The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex

EntireName: The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex
Components
  • Complex: The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 22
    • Protein or peptide: Leucine-rich glioma-inactivated protein 1
  • Ligand: CALCIUM ION

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Supramolecule #1: The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex

SupramoleculeName: The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Disintegrin and metalloproteinase domain-containing protein 22

MacromoleculeName: Disintegrin and metalloproteinase domain-containing protein 22
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.743102 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NVEEETKYIE LMIVNDHLMF KKHRLSVVHT NTYAKSVVNM ADLIYKDQLK TRIVLVAMET WATDNKFAIS ENPLITLREF MKYRRDFIK EKSDAVHLFS GSQFESSRSG AAYIGGICSL LKGGGVNEFG KTDLMAVTLA QSLAHNIGII SDKRKLASGE C KCEDTWSG ...String:
NVEEETKYIE LMIVNDHLMF KKHRLSVVHT NTYAKSVVNM ADLIYKDQLK TRIVLVAMET WATDNKFAIS ENPLITLREF MKYRRDFIK EKSDAVHLFS GSQFESSRSG AAYIGGICSL LKGGGVNEFG KTDLMAVTLA QSLAHNIGII SDKRKLASGE C KCEDTWSG CIMGDTGYYL PKKFTQCNIE EYHDFLNSGG GACLFNKPSK LLDPPECGNG FIETGEECDC GTPAECVLEG AE CCKKCTL TQDSQCSDGL CCKKCKFQPM GTVCREAVND CDIRETCSGN SSQCAPNIHK MDGYSCDGVQ GICFGGRCKT RDR QCKYIW GQKVTASDKY CYEKLNIEGT EKGNCGKDKD TWIQCNKRDV LCGYLLCTNI GNIPRLGELD GEITSTLVVQ QGRT LNCSG GHVKLEEDVD LGYVEDGTPC GPQMMCLEHR CLPVASFNFS TCLSSKEGTI CSGNGVCSNE LKCVCNRHWI GSDCN TYFP HN

UniProtKB: Disintegrin and metalloproteinase domain-containing protein 22

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Macromolecule #2: Leucine-rich glioma-inactivated protein 1

MacromoleculeName: Leucine-rich glioma-inactivated protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.570785 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DAAQPARRAR RTYEAYPAKP KCPAVCTCTK DNALCENARS IPRTVPPDVI SLSFVRSGFT EISEGSFLFT PSLQLLLFTS NSFDVISDD AFIGLPHLEY LFIENNNIKS ISRHTFRGLK SLIHLSLANN NLQTLPKDIF KGLDSLTNVD LRGNSFNCDC K LKWLVEWL ...String:
DAAQPARRAR RTYEAYPAKP KCPAVCTCTK DNALCENARS IPRTVPPDVI SLSFVRSGFT EISEGSFLFT PSLQLLLFTS NSFDVISDD AFIGLPHLEY LFIENNNIKS ISRHTFRGLK SLIHLSLANN NLQTLPKDIF KGLDSLTNVD LRGNSFNCDC K LKWLVEWL GHTNATVEDI YCEGPPEYKK RKINSLSSKD FDCIITEFAK SQDLPYQSLS IDTFSYLNDE YVVIAQPFTG KC IFLEWDH VEKTFRNYDN ITGTSTVVCK PIVIETQLYV IVAQLFGGSH IYKRDSFANK FIKIQDIEIL KIRKPNDIET FKI ENNWYF VVADSSKAGF TTIYKWNGNG FYSHQSLHAW YRDTDVEYLE IVRTPQTLRT PHLILSSSSQ RPVIYQWNKA TQLF TNQTD IPNMEDVYAV KHFSVKGDVY ICLTRFIGDS KVMKWGGSSF QDIQAMPSRG SMVFQPLQIN NYQYAILGSD YSFTQ VYNW DAEKAKFVKF QELNVQAPRS FTHVSINKRN FLFASSFKGN TQIYKHVIVD LSAKHHHHHH

UniProtKB: Leucine-rich glioma-inactivated protein 1

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 7625 / Average exposure time: 2.79627 sec. / Average electron dose: 60.8046 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 1.4000000000000001 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5y31

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 557450
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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