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- PDB-6vhh: Human Teneurin-2 and human Latrophilin-3 binary complex -

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Basic information

Entry
Database: PDB / ID: 6vhh
TitleHuman Teneurin-2 and human Latrophilin-3 binary complex
Components
  • Adhesion G protein-coupled receptor L3
  • Teneurin-2Teneurin
KeywordsMEMBRANE PROTEIN / Adhesion GPCR / synapse / Teneurin / Lphn
Function / homology
Function and homology information


retrograde trans-synaptic signaling by trans-synaptic protein complex / cell-cell adhesion via plasma-membrane adhesion molecules / positive regulation of filopodium assembly / heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules / : / neuron development / synapse assembly / cell adhesion molecule binding / filopodium / G protein-coupled receptor activity ...retrograde trans-synaptic signaling by trans-synaptic protein complex / cell-cell adhesion via plasma-membrane adhesion molecules / positive regulation of filopodium assembly / heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules / : / neuron development / synapse assembly / cell adhesion molecule binding / filopodium / G protein-coupled receptor activity / axon guidance / neuron migration / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cell-cell adhesion / PML body / cell-cell junction / cell junction / growth cone / postsynaptic membrane / carbohydrate binding / dendritic spine / cell surface receptor signaling pathway / neuron projection / G protein-coupled receptor signaling pathway / protein heterodimerization activity / axon / signaling receptor binding / dendrite / glutamatergic synapse / synapse / calcium ion binding / Golgi apparatus / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / signal transduction / protein homodimerization activity / membrane / nucleus / plasma membrane
Similarity search - Function
Teneurin-2 / Rhamnose-binding lectin domain (RBL) / Teneurin intracellular, N-terminal / Teneurin Intracellular Region / Teneurin N-terminal domain profile. / Tox-GHH domain / GHH signature containing HNH/Endo VII superfamily nuclease toxin / GPCR, family 2, latrophilin, C-terminal / GPCR, family 2, latrophilin / Latrophilin Cytoplasmic C-terminal region ...Teneurin-2 / Rhamnose-binding lectin domain (RBL) / Teneurin intracellular, N-terminal / Teneurin Intracellular Region / Teneurin N-terminal domain profile. / Tox-GHH domain / GHH signature containing HNH/Endo VII superfamily nuclease toxin / GPCR, family 2, latrophilin, C-terminal / GPCR, family 2, latrophilin / Latrophilin Cytoplasmic C-terminal region / D-galactoside/L-rhamnose binding SUEL lectin domain superfamily / YD repeat / GAIN domain, N-terminal / GPCR-Autoproteolysis INducing (GAIN) domain / D-galactoside/L-rhamnose binding SUEL lectin domain / Galactose binding lectin domain / SUEL-type lectin domain profile. / Olfactomedin-like domain / Olfactomedin-like domain / Olfactomedin-like domain profile. / Olfactomedin-like domains / Rhs repeat-associated core / Carboxypeptidase-like, regulatory domain superfamily / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GPS domain profile. / G-protein-coupled receptor proteolytic site domain / Quinoprotein amine dehydrogenase, beta chain-like / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / Six-bladed beta-propeller, TolB-like / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
Adhesion G protein-coupled receptor L3 / Teneurin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsXie, Y. / Li, J. / Arac, D. / Zhao, M.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM120322 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM134035-01 United States
American Heart Association19POST34380439/Jingxian Li/2019-2020 United States
CitationJournal: Nat Commun / Year: 2020
Title: Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism.
Authors: Jingxian Li / Yuan Xie / Shaleeka Cornelius / Xian Jiang / Richard Sando / Szymon P Kordon / Man Pan / Katherine Leon / Thomas C Südhof / Minglei Zhao / Demet Araç /
Abstract: The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs/ADGRLs) promotes excitatory synapse formation when LPHNs simultaneously interact with FLRTs. ...The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs/ADGRLs) promotes excitatory synapse formation when LPHNs simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within TENs abolishes the TEN-LPHN interaction and switches TEN function to specify inhibitory synapses. How alternative-splicing regulates TEN-LPHN interaction remains unclear. Here, we report the 2.9 Å resolution cryo-EM structure of the TEN2-LPHN3 complex, and describe the trimeric TEN2-LPHN3-FLRT3 complex. The structure reveals that the N-terminal lectin domain of LPHN3 binds to the TEN2 barrel at a site far away from the alternatively spliced region. Alternative-splicing regulates the TEN2-LPHN3 interaction by hindering access to the LPHN-binding surface rather than altering it. Strikingly, mutagenesis of the LPHN-binding surface of TEN2 abolishes the LPHN3 interaction and impairs excitatory but not inhibitory synapse formation. These results suggest that a multi-level coincident binding mechanism mediated by a cryptic adhesion complex between TENs and LPHNs regulates synapse specificity.
History
DepositionJan 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2020Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_chiral / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _database_PDB_caveat.text / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_chiral.auth_asym_id / _pdbx_validate_chiral.auth_seq_id / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Assembly

Deposited unit
A: Teneurin-2
B: Adhesion G protein-coupled receptor L3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)314,57410
Polymers311,4642
Non-polymers3,1108
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Size-exclusion chromatograms prove the formation of a binary complex between soluble Teneurin2 and Latrophilin3.
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Teneurin-2 / Teneurin / Ten-2 / Protein Odd Oz/ten-m homolog 2 / Tenascin-M2 / Ten-m2 / Teneurin transmembrane protein 2


Mass: 216254.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TENM2, KIAA1127, ODZ2, TNM2 / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NT68
#2: Protein Adhesion G protein-coupled receptor L3 / Calcium-independent alpha-latrotoxin receptor 3 / CIRL-3 / Latrophilin-3 / Lectomedin-3


Mass: 95209.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADGRL3, KIAA0768, LEC3, LPHN3 / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9HAR2

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Sugars , 4 types, 8 molecules

#3: Polysaccharide alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-GlcpNAc]{[(4+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][a-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN

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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: Binary complex of human Teneurin-2 with human Latrophilin-3 extracellular domain
Type: COMPLEX
Details: The binary complex includes human Teneurin2 (TENM2) (Teneurin without alternative splice sequence NKEFKHS) and human Latrophilin3 (LPHN3/ADGRL3) with an alternative splice sequence KVEQK ...Details: The binary complex includes human Teneurin2 (TENM2) (Teneurin without alternative splice sequence NKEFKHS) and human Latrophilin3 (LPHN3/ADGRL3) with an alternative splice sequence KVEQK between lectin domain and olfactomedin domain.
Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.314 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper) / Cell: Hi5
Buffer solutionpH: 8.5
SpecimenConc.: 2.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 81000 X / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 4.2 sec. / Electron dose: 60.1 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 5402

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Processing

EM software
IDNameVersionCategory
4RELION3.0.8CTF correction
10RELION3.0.8initial Euler assignment
11RELION3.0.8final Euler assignment
12RELION3.0.8classification
13RELION3.0.83D reconstruction
CTF correctionDetails: CTF correction was done in Relion reconstruction / Type: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 4475958
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 436208 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 52.62 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01514522
ELECTRON MICROSCOPYf_angle_d1.051119742
ELECTRON MICROSCOPYf_chiral_restr0.22872272
ELECTRON MICROSCOPYf_plane_restr0.01362520
ELECTRON MICROSCOPYf_dihedral_angle_d21.70215237

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