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- PDB-9qnr: Cryo-EM structure of TTYH3 in GDN after incubation with ApoE, map2 -

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Basic information

Entry
Database: PDB / ID: 9qnr
TitleCryo-EM structure of TTYH3 in GDN after incubation with ApoE, map2
ComponentsProtein tweety homolog 3
KeywordsMEMBRANE PROTEIN / lipid interactions
Function / homology
Function and homology information


volume-sensitive chloride channel activity / L-glutamate transmembrane transport / intracellularly calcium-gated chloride channel activity / chloride transport / chloride channel activity / chloride channel complex / Stimuli-sensing channels / monoatomic ion transmembrane transport / calcium ion binding / extracellular exosome / plasma membrane
Similarity search - Function
Protein tweety homolog 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsSukalskaia, A. / Pugnetti, A. / Dutzler, R. / Plochberger, B. / Weber, F. / Karner, A.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: Nature / Year: 2025
Title: Interactions between TTYH2 and APOE facilitate endosomal lipid transfer.
Authors: Anastasiia Sukalskaia / Andreas Karner / Anna Pugnetti / Florian Weber / Birgit Plochberger / Raimund Dutzler /
Abstract: The Tweety homologues (TTYHs) constitute a family of eukaryotic membrane proteins that, on the basis of structural features, were recently proposed to contribute to lipid transfer between soluble ...The Tweety homologues (TTYHs) constitute a family of eukaryotic membrane proteins that, on the basis of structural features, were recently proposed to contribute to lipid transfer between soluble carriers and cellular membranes. However, in the absence of supporting data, this function was hypothetical. Here through pull-down of endogenous proteins, we identify APOE as the interaction partner of human TTYH2. Subcellular fractionation and immunocytochemistry assays showed that both proteins colocalize in endosomal compartments. Characterization of the specific interaction between APOE and TTYH2 through binding assays and structural studies enabled us to identify an epitope in an extended domain of TTYH2 that faces the endosomal lumen. Structures of complexes with APOE-containing lipoprotein particles revealed a binding mode that places lipids in a suitable position to facilitate their diffusion into the membrane. Moreover, in vitro studies revealed that lipid transfer is accelerated by TTYH2. Collectively, our findings indicate that TTYH2 has a role in the unloading of APOE-containing lipoproteins after they are endocytosed. These results define a new protein class that facilitates the extraction of lipids from and their insertion into cellular membranes. Although ubiquitous, this process could be of particular relevance in the brain, where APOE is involved in the transfer of lipids between astrocytes and neurons.
History
DepositionMar 25, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 21, 2025Provider: repository / Type: Initial release
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Revision 1.0May 21, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 21, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein tweety homolog 3
B: Protein tweety homolog 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,2868
Polymers129,5532
Non-polymers1,7346
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 Protein tweety homolog 3 / hTTY3 / Volume-regulated anion channel subunit TTYH3


Mass: 64776.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: contains C-terminal Myc-tag followed by SBP-tag / Source: (gene. exp.) Homo sapiens (human) / Gene: TTYH3, KIAA1691 / Cell line (production host): HEK293 GNTI- / Production host: Homo sapiens (human) / References: UniProt: Q9C0H2
#2: 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.: 2
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)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / 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
Has ligand of interestN
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: TTYH3 dimer purified in GDN / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.13 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293 GNTI-
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMsodium chlorideNaCl1
210 mMhepesHepes1
350 mMglycodiosgeninGDN1
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: This sample contained TTYH3 mixed with apolipoprotein E. No complex formation between the two proteins was detected. The resulting maps display only TTYH3 density.
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 68 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.2_5419 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 547367 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 63.41 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00336370
ELECTRON MICROSCOPYf_angle_d0.50138716
ELECTRON MICROSCOPYf_chiral_restr0.03621054
ELECTRON MICROSCOPYf_plane_restr0.00361072
ELECTRON MICROSCOPYf_dihedral_angle_d11.94442326

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