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- PDB-9g71: Cryo-EM structure of TTYH2 in complex with lipids in GDN -

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Basic information

Entry
Database: PDB / ID: 9g71
TitleCryo-EM structure of TTYH2 in complex with lipids in GDN
ComponentsProtein tweety homolog 2
KeywordsMEMBRANE PROTEIN / complex / sybody / nanobody / TTYH2
Function / homology
Function and homology information


volume-sensitive chloride channel activity / L-glutamate transmembrane transport / intracellularly calcium-gated chloride channel activity / chloride channel complex / Stimuli-sensing channels / calcium ion binding / plasma membrane
Similarity search - Function
CHOLESTEROL / Chem-CPL / DIUNDECYL PHOSPHATIDYL CHOLINE / Protein tweety homolog 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsSukalskaia, A. / Weber, F. / Plochberger, B. / Dutzler, R.
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
DepositionJul 19, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 21, 2025Provider: 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 2
B: Protein tweety homolog 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,76536
Polymers132,0002
Non-polymers17,76534
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

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Protein , 1 types, 2 molecules AB

#1: Protein Protein tweety homolog 2 / hTTY2 / Volume-regulated anion channel subunit TTYH2


Mass: 66000.039 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTYH2, C17orf29 / Production host: Homo sapiens (human) / References: UniProt: Q9BSA4

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Sugars , 2 types, 8 molecules

#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.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-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 / Feature type: SUBJECT OF INVESTIGATION
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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Non-polymers , 3 types, 26 molecules

#4: Chemical
ChemComp-PLC / DIUNDECYL PHOSPHATIDYL CHOLINE


Mass: 622.834 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C32H65NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#5: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CPL / 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PALMITOYL-LINOLEOYL PHOSPHATIDYLCHOLINE


Mass: 758.060 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C42H80NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM

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Details

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: TTYH2 purified in GDN with lipids / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.066 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMsodium chlorideNaCl1
210 mMhepesHEPES1
350 uMglycodiosgeninGDN1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE / Humidity: 100 %

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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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm / C2 aperture diameter: 50 µm
Image recordingElectron dose: 63 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2192921 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 69.62 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00377446
ELECTRON MICROSCOPYf_angle_d0.451210032
ELECTRON MICROSCOPYf_chiral_restr0.03471144
ELECTRON MICROSCOPYf_plane_restr0.00321104
ELECTRON MICROSCOPYf_dihedral_angle_d17.43752043

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