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- EMDB-53249: Cryo-EM structure of TTYH3 in GDN after incubation with ApoE, map2 -

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Basic information

Entry
Database: EMDB / ID: EMD-53249
TitleCryo-EM structure of TTYH3 in GDN after incubation with ApoE, map2
Map dataTTYH3
Sample
  • Complex: TTYH3 dimer purified in GDN
    • Protein or peptide: Protein tweety homolog 3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsSukalskaia A / Pugnetti A / Dutzler R / Plochberger B / Weber F / Karner A
Funding support Switzerland, 1 items
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, 2025-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53249.png

Downloads & links

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Map

FileDownload / File: emd_53249.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTTYH3
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 220 pix.
= 286.44 Å		1.3 Å/pix.
x 220 pix.
= 286.44 Å		1.3 Å/pix.
x 220 pix.
= 286.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.302 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.9403958 - 3.2857575
Average (Standard dev.)-0.00017912095 (±0.055201173)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 286.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: TTYH3 halfmap2

Fileemd_53249_half_map_1.map
AnnotationTTYH3 halfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: TTYH3 halfmap1

Fileemd_53249_half_map_2.map
AnnotationTTYH3 halfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TTYH3 dimer purified in GDN

EntireName: TTYH3 dimer purified in GDN
Components
  • Complex: TTYH3 dimer purified in GDN
    • Protein or peptide: Protein tweety homolog 3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: TTYH3 dimer purified in GDN

SupramoleculeName: TTYH3 dimer purified in GDN / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130 KDa

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Macromolecule #1: Protein tweety homolog 3

MacromoleculeName: Protein tweety homolog 3 / type: protein_or_peptide / ID: 1 / Details: contains C-terminal Myc-tag followed by SBP-tag / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.776391 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSAGVSYAAP WWVSLLHRLP HFDLSWEATS SQFRPEDTDY QQALLLLGAA ALACLALDLL FLLFYSFWLC CRRRKSEEHL DADCCCTAW CVIIATLVCS AGIAVGFYGN GETSDGIHRA TYSLRHANRT VAGVQDRVWD TAVGLNHTAE PSLQTLERQL A GRPEPLRA ...String:
MSAGVSYAAP WWVSLLHRLP HFDLSWEATS SQFRPEDTDY QQALLLLGAA ALACLALDLL FLLFYSFWLC CRRRKSEEHL DADCCCTAW CVIIATLVCS AGIAVGFYGN GETSDGIHRA TYSLRHANRT VAGVQDRVWD TAVGLNHTAE PSLQTLERQL A GRPEPLRA VQRLQGLLET LLGYTAAIPF WRNTAVSLEV LAEQVDLYDW YRWLGYLGLL LLDVIICLLV LVGLIRSSKG IL VGVCLLG VLALVISWGA LGLELAVSVG SSDFCVDPDA YVTKMVEEYS VLSGDILQYY LACSPRAANP FQQKLSGSHK ALV EMQDVV AELLRTVPWE QPATKDPLLR VQEVLNGTEV NLQHLTALVD CRSLHLDYVQ ALTGFCYDGV EGLIYLALFS FVTA LMFSS IVCSVPHTWQ QKRGPDEDGE EEAAPGPRQA HDSLYRVHMP SLYSCGSSYG SETSIPAAAH TVSNAPVTEY MSQNA NFQN PRCENTPLIG RESPPPSYTS SMRAKYLATS QPRPDSSGSH ALEVLFQGPQ GTEQKLISEE DLRGASMDEK TTGWRG GHV VEGLAGELEQ LRARLEHHPQ GQREP

UniProtKB: Protein tweety homolog 3

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration1.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
10.0 mMHepeshepes
50.0 mMGDNglycodiosgenin
GridMaterial: GOLD / Mesh: 200
VitrificationCryogen name: NITROGEN / Instrument: FEI VITROBOT MARK IV
DetailsThis sample contained TTYH3 mixed with apolipoprotein E. No complex formation between the two proteins was detected. The resulting maps display only TTYH3 density.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 68.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 547367
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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