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- EMDB-24688: Cryo-EM structure of a TTYH2 cis-dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-24688
TitleCryo-EM structure of a TTYH2 cis-dimer
Map dataTweety Homolog Proteins TTYH2 and TTYH3 in lipid nanodiscs
Sample
  • Complex: TTYH2
    • Protein or peptide: Protein tweety homolog 2
  • Ligand: CALCIUM IONCalcium
Function / homologyvolume-sensitive chloride channel activity / Tweety / Tweety / intracellularly calcium-gated chloride channel activity / Stimuli-sensing channels / chloride channel complex / membrane / plasma membrane / Protein tweety homolog 2
Function and homology information
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLi B / Brohawn SG / Hoel CM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM123496 United States
CitationJournal: Nat Commun / Year: 2021
Title: Structures of tweety homolog proteins TTYH2 and TTYH3 reveal a Ca-dependent switch from intra- to intermembrane dimerization.
Authors: Baobin Li / Christopher M Hoel / Stephen G Brohawn /
Abstract: Tweety homologs (TTYHs) comprise a conserved family of transmembrane proteins found in eukaryotes with three members (TTYH1-3) in vertebrates. They are widely expressed in mammals including at high ...Tweety homologs (TTYHs) comprise a conserved family of transmembrane proteins found in eukaryotes with three members (TTYH1-3) in vertebrates. They are widely expressed in mammals including at high levels in the nervous system and have been implicated in cancers and other diseases including epilepsy, chronic pain, and viral infections. TTYHs have been reported to form Ca- and cell volume-regulated anion channels structurally distinct from any characterized protein family with potential roles in cell adhesion, migration, and developmental signaling. To provide insight into TTYH family structure and function, we determined cryo-EM structures of Mus musculus TTYH2 and TTYH3 in lipid nanodiscs. TTYH2 and TTYH3 adopt a previously unobserved fold which includes an extended extracellular domain with a partially solvent exposed pocket that may be an interaction site for hydrophobic molecules. In the presence of Ca, TTYH2 and TTYH3 form homomeric cis-dimers bridged by extracellularly coordinated Ca. Strikingly, in the absence of Ca, TTYH2 forms trans-dimers that span opposing membranes across a ~130 Å intermembrane space as well as a monomeric state. All TTYH structures lack ion conducting pathways and we do not observe TTYH2-dependent channel activity in cells. We conclude TTYHs are not pore forming subunits of anion channels and their function may involve Ca-dependent changes in quaternary structure, interactions with hydrophobic molecules near the extracellular membrane surface, and/or association with additional protein partners.
History
DepositionAug 15, 2021-
Header (metadata) releaseAug 25, 2021-
Map releaseAug 25, 2021-
UpdateMar 9, 2022-
Current statusMar 9, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 7
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 7
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7rtt
  • Surface level: 7
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7rtt
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24688.png

Downloads & links

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Map

FileDownload / File: emd_24688.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTweety Homolog Proteins TTYH2 and TTYH3 in lipid nanodiscs
Voxel sizeX=Y=Z: 1.137 Å
Density
Contour LevelBy AUTHOR: 7.0 / Movie #1: 7
Minimum - Maximum-37.14306 - 58.931305
Average (Standard dev.)1.6489737e-12 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 291.072 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1371.1371.137
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z291.072291.072291.072
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-37.14358.9310.000

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Supplemental data

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Sample components

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Entire : TTYH2

EntireName: TTYH2
Components
  • Complex: TTYH2
    • Protein or peptide: Protein tweety homolog 2
  • Ligand: CALCIUM IONCalcium

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Supramolecule #1: TTYH2

SupramoleculeName: TTYH2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Mammalia (mammals)

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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: Mus musculus (house mouse)
Molecular weightTheoretical: 59.941434 KDa
Recombinant expressionOrganism: Mammalia (mammals)
SequenceString: PAARVEYIAP WWVVWLHSVP HLGLRLQRVD STFSPGDETY QESLLFLGVL AAIGLGLNLI FLTVYLVCTC CCRRDHTVQT KQQESCCVT WTAVVAGLLC CAAVGVGFYG NSETNDGMHQ LIYSLDNANH TFSGMDELVS ANTQRMKVDL EQHLARLSEI I AARGDYIQ ...String:
PAARVEYIAP WWVVWLHSVP HLGLRLQRVD STFSPGDETY QESLLFLGVL AAIGLGLNLI FLTVYLVCTC CCRRDHTVQT KQQESCCVT WTAVVAGLLC CAAVGVGFYG NSETNDGMHQ LIYSLDNANH TFSGMDELVS ANTQRMKVDL EQHLARLSEI I AARGDYIQ TLKFMQQMAG NVVSQLSGLP VWREVTTQLT KLSHQTAYVE YYRWLSYLLL FILDLVICLV TCLGLARRSK CL LASMLCC GILTLILSWA SLAADAAAAV GTSDFCMAPD IYILNNTGSQ INSEVTRYYL HCSQSLISPF QQSLTTFQRS LTT MQIQVG GLLQFAVPLF PTAEKDLLGI QLLLNNSEIS LHQLTAMLDC RGLHKDYLDA LTGICYDGIE GLLFLGLFSL LAAL AFSTL TCAGPRAWKY FINRDRDYDD IDDDDPFNPQ ARRIAAHNPT RGQLHSFCSY SSGLGSQCSL QPPSQTISNA PVSEY MNQA ILFGGNPRYE NVPLIGRGSP PPTYSPSMRP TYMSVADEHL RHYEFPSSNS LEVLFQ

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

Concentration1.1 mg/mL
BufferpH: 8 / Details: 20 mM Tris pH 8.0, 150 mM NaCl, 1 mM CaCl2
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TECNAI ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.0038 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND (ver. 4.1.13)
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3.2.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 96342

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7rtt:
Cryo-EM structure of a TTYH2 cis-dimer

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