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- EMDB-46724: Cryo-EM structure of human ABCB6 transporter in an inward-facing ... -

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Basic information

Entry
Database: EMDB / ID: EMD-46724
TitleCryo-EM structure of human ABCB6 transporter in an inward-facing conformation
Map datafull map
Sample
  • Complex: ABCB6
    • Protein or peptide: ATP-binding cassette sub-family B member 6
  • Ligand: CHOLESTEROL HEMISUCCINATE
Keywordstransporter / ATPase / MEMBRANE PROTEIN
Function / homology
Function and homology information


Defective ABCB6 causes MCOPCB7 / cellular detoxification of cadmium ion / Mitochondrial ABC transporters / tetrapyrrole metabolic process / ABC-type heme transporter / porphyrin-containing compound metabolic process / tetrapyrrole binding / heme metabolic process / porphyrin-containing compound biosynthetic process / heme transport ...Defective ABCB6 causes MCOPCB7 / cellular detoxification of cadmium ion / Mitochondrial ABC transporters / tetrapyrrole metabolic process / ABC-type heme transporter / porphyrin-containing compound metabolic process / tetrapyrrole binding / heme metabolic process / porphyrin-containing compound biosynthetic process / heme transport / melanosome assembly / ABC-type heme transporter activity / heme transmembrane transport / melanosome membrane / multivesicular body membrane / mitochondrial envelope / endolysosome membrane / vacuolar membrane / skin development / efflux transmembrane transporter activity / intracellular copper ion homeostasis / ABC-type transporter activity / ATP-binding cassette (ABC) transporter complex / brain development / transmembrane transport / early endosome membrane / mitochondrial outer membrane / intracellular iron ion homeostasis / endosome / Golgi membrane / lysosomal membrane / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / Golgi apparatus / ATP hydrolysis activity / mitochondrion / extracellular exosome / nucleoplasm / ATP binding / plasma membrane / cytosol
Similarity search - Function
Mitochondrial ABC-transporter, N-terminal five TM domain / Mitochondrial ABC-transporter N-terminal five TM region / Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter ...Mitochondrial ABC-transporter, N-terminal five TM domain / Mitochondrial ABC-transporter N-terminal five TM region / Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ATP-binding cassette sub-family B member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsShaik MM / Myasnikov A / Oldham ML / Baril SA / Kalathur RC / Schuetz JD
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: The role of ATP-binding Cassette subfamily B member 6 in the inner ear.
Authors: Stefanie A Baril / Katie A Wilson / Md Munan Shaik / Yu Fukuda / Robyn A Umans / Alessandro Barbieri / John Lynch / Tomoka Gose / Alexander Myasnikov / Michael L Oldham / Yao Wang / Jingwen ...Authors: Stefanie A Baril / Katie A Wilson / Md Munan Shaik / Yu Fukuda / Robyn A Umans / Alessandro Barbieri / John Lynch / Tomoka Gose / Alexander Myasnikov / Michael L Oldham / Yao Wang / Jingwen Zhu / Jie Fang / Jian Zuo / Ravi C Kalathur / Robert C Ford / Allison Coffin / Michael R Taylor / Megan L O'Mara / John D Schuetz /
Abstract: ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also ...ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function.
History
DepositionAug 23, 2024-
Header (metadata) releaseNov 20, 2024-
Map releaseNov 20, 2024-
UpdateDec 4, 2024-
Current statusDec 4, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46724.png

Downloads & links

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Map

FileDownload / File: emd_46724.map.gz / Format: CCP4 / Size: 55.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfull map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 244 pix.
= 265.277 Å		1.09 Å/pix.
x 244 pix.
= 265.277 Å		1.09 Å/pix.
x 244 pix.
= 265.277 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0872 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.7515988 - 1.0354817
Average (Standard dev.)0.0019492685 (±0.020727387)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions244244244
Spacing244244244
CellA=B=C: 265.27682 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: DeepEMhancer map

Fileemd_46724_additional_1.map
AnnotationDeepEMhancer map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_46724_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_46724_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : ABCB6

EntireName: ABCB6
Components
  • Complex: ABCB6
    • Protein or peptide: ATP-binding cassette sub-family B member 6
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: ABCB6

SupramoleculeName: ABCB6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: homodimer
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 189.761 KDa

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Macromolecule #1: ATP-binding cassette sub-family B member 6

MacromoleculeName: ATP-binding cassette sub-family B member 6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: ABC-type heme transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.971133 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVTVGNYCEA EGPVGPAWMQ DGLSPCFFFT LVPSTRMALG TLALVLALPC RRRERPAGAD SLSWGAGPRI SPYVLQLLLA TLQAALPLA GLAGRVGTAR GAPLPSYLLL ASVLESLAGA CGLWLLVVER SQARQRLAMG IWIKFRHSPG LLLLWTVAFA A ENLALVSW ...String:
MVTVGNYCEA EGPVGPAWMQ DGLSPCFFFT LVPSTRMALG TLALVLALPC RRRERPAGAD SLSWGAGPRI SPYVLQLLLA TLQAALPLA GLAGRVGTAR GAPLPSYLLL ASVLESLAGA CGLWLLVVER SQARQRLAMG IWIKFRHSPG LLLLWTVAFA A ENLALVSW NSPQWWWARA DLGQQVQFSL WVLRYVVSGG LFVLGLWAPG LRPQSYTLQV HEEDQDVERS QVRSAAQQST WR DFGRKLR LLSGYLWPRG SPALQLVVLI CLGLMGLERA LNVLVPIFYR NIVNLLTEKA PWNSLAWTVT SYVFLKFLQG GGT GSTGFV SNLRTFLWIR VQQFTSRRVE LLIFSHLHEL SLRWHLGRRT GEVLRIADRG TSSVTGLLSY LVFNVIPTLA DIII GIIYF SMFFNAWFGL IVFLCMSLYL TLTIVVTEWR TKFRRAMNTQ ENATRARAVD SLLNFETVKY YNAESYEVER YREAI IKYQ GLEWKSSASL VLLNQTQNLV IGLGLLAGSL LCAYFVTEQK LQVGDYVLFG TYIIQLYMPL NWFGTYYRMI QTNFID MEN MFDLLKEETE VKDLPGAGPL RFQKGRIEFE NVHFSYADGR ETLQDVSFTV MPGQTLALVG PSGAGKSTIL RLLFRFY DI SSGCIRIDGQ DISQVTQASL RSHIGVVPQD TVLFNDTIAD NIRYGRVTAG NDEVEAAAQA AGIHDAIMAF PEGYRTQV G ERGLKLSGGE KQRVAIARTI LKAPGIILLD EATSALDTSN ERAIQASLAK VCANRTTIVV AHRLSTVVNA DQILVIKDG CIVERGRHEA LLSRGGVYAD MWQLQQGQEE TSEDTKPQTM ERDYKDDDDK

UniProtKB: ATP-binding cassette sub-family B member 6

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 20 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

Concentration3.6 mg/mL
BufferpH: 7.5
Component:
ConcentrationName
10.0 mMTris-HCl
150.0 mMsodium chloride
0.2 mMdodecylmaltoside
0.041 mMcholesteryl hemisuccinate

Details: 10 mM Tris, pH 7.5, 150 mM NaCl, 0.01% w/v DDM, 0.002% w/v CHS
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
TemperatureMin: 100.0 K
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 1 / Number real images: 7013 / Average exposure time: 1.1 sec. / Average electron dose: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 25.0 µm / Nominal defocus min: 5.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3344054 / Details: blob picker
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1587831
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC / Details: heterorefinement
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-9dbq:
Cryo-EM structure of human ABCB6 transporter in an inward-facing conformation

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