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- PDB-9kzc: Cryo-EM structure of the LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex -

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Basic information

Entry
Database: PDB / ID: 9kzc
TitleCryo-EM structure of the LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex
Components
  • Disintegrin and metalloproteinase domain-containing protein 22
  • Leucine-rich glioma-inactivated protein 1
KeywordsCELL ADHESION / epilepsy / synapse / adam / eptp / ed40
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsYamaguchi, T. / Okatsu, K. / Kubota, M. / Mitsumori, A. / Yamagata, A. / Fukai, S.
Funding support Japan, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Disintegrin and metalloproteinase domain-containing protein 22
B: Leucine-rich glioma-inactivated protein 1
D: Leucine-rich glioma-inactivated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,0457
Polymers178,8853
Non-polymers1604
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Disintegrin and metalloproteinase domain-containing protein 22 / ADAM 22 / Metalloproteinase-disintegrin ADAM22-3 / Metalloproteinase-like / disintegrin-like / and ...ADAM 22 / Metalloproteinase-disintegrin ADAM22-3 / Metalloproteinase-like / disintegrin-like / and cysteine-rich protein 2


Mass: 53743.102 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 233-729
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM22, MDC2 / Production host: Homo sapiens (human) / References: UniProt: Q9P0K1
#2: Protein Leucine-rich glioma-inactivated protein 1 / Epitempin-1


Mass: 62570.785 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 37-557 / Mutation: R470A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LGI1, EPT, UNQ775/PRO1569 / Production host: Homo sapiens (human) / References: UniProt: O95970
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: The LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1700 nm / Nominal defocus min: 1400 nm
Image recordingAverage exposure time: 2.79627 sec. / Electron dose: 60.8046 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 7625

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 557450 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028011
ELECTRON MICROSCOPYf_angle_d0.45510826
ELECTRON MICROSCOPYf_dihedral_angle_d4.3511061
ELECTRON MICROSCOPYf_chiral_restr0.0431187
ELECTRON MICROSCOPYf_plane_restr0.0031394

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