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- EMDB-51106: Cryo-EM structure of TTYH2 in complex with sybody 1 in GDN -

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Basic information

Entry
Database: EMDB / ID: EMD-51106
TitleCryo-EM structure of TTYH2 in complex with sybody 1 in GDN
Map data
Sample
  • Complex: TTYH2 purified in GDN in complex with sybody 1
    • Complex: synthetic nanobody selected for binding TTYH2
      • Protein or peptide: sybody 1
    • Complex: TTYH2 purified in GDN
      • Protein or peptide: Protein tweety homolog 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscomplex / sybody / nanobody / TTYH2 / MEMBRANE PROTEIN
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
Protein tweety homolog 2
Similarity search - Component
Biological speciesVicugna pacos (alpaca) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsSukalskaia A / Weber F / Plochberger B / Dutzler R
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
DepositionJul 19, 2024-
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_51106.png

Downloads & links

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Map

FileDownload / File: emd_51106.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
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: 0.11
Minimum - Maximum-0.67518103 - 1.2357175
Average (Standard dev.)-0.0009589014 (±0.02419575)
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: #2

Fileemd_51106_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_51106_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : TTYH2 purified in GDN in complex with sybody 1

EntireName: TTYH2 purified in GDN in complex with sybody 1
Components
  • Complex: TTYH2 purified in GDN in complex with sybody 1
    • Complex: synthetic nanobody selected for binding TTYH2
      • Protein or peptide: sybody 1
    • Complex: TTYH2 purified in GDN
      • Protein or peptide: Protein tweety homolog 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: TTYH2 purified in GDN in complex with sybody 1

SupramoleculeName: TTYH2 purified in GDN in complex with sybody 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Molecular weightTheoretical: 66 KDa

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Supramolecule #2: synthetic nanobody selected for binding TTYH2

SupramoleculeName: synthetic nanobody selected for binding TTYH2 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Vicugna pacos (alpaca)

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Supramolecule #3: TTYH2 purified in GDN

SupramoleculeName: TTYH2 purified in GDN / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein tweety homolog 2

MacromoleculeName: Protein tweety homolog 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.000039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSQAARVDYI APWWVVWLHS VPHVGLRLQP VNSTFSPGDE SYQESLLFLG LVAAVCLGLN LIFLVAYLVC ACHCRRDDAV QTKQHHSCC ITWTAVVAGL ICCAAVGVGF YGNSETNDGA YQLMYSLDDA NHTFSGIDAL VSGTTQKMKV DLEQHLARLS E IFAARGDY ...String:
MSQAARVDYI APWWVVWLHS VPHVGLRLQP VNSTFSPGDE SYQESLLFLG LVAAVCLGLN LIFLVAYLVC ACHCRRDDAV QTKQHHSCC ITWTAVVAGL ICCAAVGVGF YGNSETNDGA YQLMYSLDDA NHTFSGIDAL VSGTTQKMKV DLEQHLARLS E IFAARGDY LQTLKFIQQM AGSVVVQLSG LPVWREVTME LTKLSDQTGY VEYYRWLSYL LLFILDLVIC LIACLGLAKR SK CLLASML CCGALSLLLS WASLAADGSA AVATSDFCVA PDTFILNVTE GQISTEVTRY YLYCSQSGSS PFQQTLTTFQ RAL TTMQIQ VAGLLQFAVP LFSTAEEDLL AIQLLLNSSE SSLHQLTAMV DCRGLHKDYL DALAGICYDG LQGLLYLGLF SFLA ALAFS TMICAGPRAW KHFTTRNRDY DDIDDDDPFN PQAWRMAAHS PPRGQLHSFC SYSSGLGSQT SLQPPAQTIS NAPVS EYMN QAMLFGRNPR YENVPLIGRA SPPPTYSPSM RATYLSVADE HLRHYGNQFP AALEVLFQGP QGTEQKLISE EDLRGA SMD EKTTGWRGGH VVEGLAGELE QLRARLEHHP QGQREP

UniProtKB: Protein tweety homolog 2

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Macromolecule #2: sybody 1

MacromoleculeName: sybody 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 15.436077 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SQVQLVESGG GLVQAGGSLR LSCTASGFPV AFAQMKWYRQ APGKEREWVA AIWSMGNETT YADSVKGRFT ISRDNAKNTV YLQMNSLKP EDTAVYYCAV EVGYGYHGQG TQVTVSAGRA GEQKLISEED LNSAVDHHHH HH

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / 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

BufferpH: 7.4
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
10.0 mMHEPEShepes
50.0 uMGDNglycodiosgenin
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 68.48 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination 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: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 75814
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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