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- EMDB-9937: Cryo-EM structure of the human P4-type flippase ATP8A1-CDC50 (E1-... -

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Basic information

Entry
Database: EMDB / ID: EMD-9937
TitleCryo-EM structure of the human P4-type flippase ATP8A1-CDC50 (E1-ADP-Pi state)
Map data
Sample
  • Complex: ATP8A1-CDC50a
    • Protein or peptide: Phospholipid-transporting ATPase
    • Protein or peptide: Cell cycle control protein 50A
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: TETRAFLUOROALUMINATE ION
  • Ligand: MAGNESIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL HEMISUCCINATE
Function / homology
Function and homology information


aminophospholipid translocation / positive regulation of phospholipid translocation / aminophospholipid flippase activity / aminophospholipid transport / chromaffin granule membrane / phosphatidylserine flippase activity / protein localization to endosome / phosphatidylserine floppase activity / phospholipid-translocating ATPase complex / ATPase-coupled intramembrane lipid transporter activity ...aminophospholipid translocation / positive regulation of phospholipid translocation / aminophospholipid flippase activity / aminophospholipid transport / chromaffin granule membrane / phosphatidylserine flippase activity / protein localization to endosome / phosphatidylserine floppase activity / phospholipid-translocating ATPase complex / ATPase-coupled intramembrane lipid transporter activity / positive regulation of protein exit from endoplasmic reticulum / xenobiotic transmembrane transport / phospholipid transport / ATPase-coupled monoatomic cation transmembrane transporter activity / P-type phospholipid transporter / phospholipid translocation / azurophil granule membrane / transport vesicle membrane / Ion transport by P-type ATPases / organelle membrane / transport across blood-brain barrier / endomembrane system / specific granule membrane / monoatomic ion transmembrane transport / learning / trans-Golgi network / positive regulation of neuron projection development / synaptic vesicle membrane / late endosome membrane / cytoplasmic vesicle / early endosome membrane / positive regulation of cell migration / apical plasma membrane / intracellular membrane-bounded organelle / Neutrophil degranulation / structural molecule activity / Golgi apparatus / magnesium ion binding / endoplasmic reticulum / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane / cytosol
Similarity search - Function
CDC50/LEM3 family / LEM3 (ligand-effect modulator 3) family / CDC50 family / P-type ATPase, subfamily IV / P-type ATPase, C-terminal / P-type ATPase, N-terminal / Phospholipid-translocating ATPase N-terminal / Phospholipid-translocating P-type ATPase C-terminal / Cation transport ATPase (P-type) / E1-E2 ATPase / P-type ATPase, haloacid dehalogenase domain ...CDC50/LEM3 family / LEM3 (ligand-effect modulator 3) family / CDC50 family / P-type ATPase, subfamily IV / P-type ATPase, C-terminal / P-type ATPase, N-terminal / Phospholipid-translocating ATPase N-terminal / Phospholipid-translocating P-type ATPase C-terminal / Cation transport ATPase (P-type) / E1-E2 ATPase / P-type ATPase, haloacid dehalogenase domain / P-type ATPase, phosphorylation site / P-type ATPase, cytoplasmic domain N / E1-E2 ATPases phosphorylation site. / P-type ATPase, A domain superfamily / P-type ATPase / P-type ATPase, transmembrane domain superfamily / HAD superfamily / HAD-like superfamily
Similarity search - Domain/homology
Phospholipid-transporting ATPase / Cell cycle control protein 50A / Phospholipid-transporting ATPase IA
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsHiraizumi M / Yamashita K / Nishizawa T / Nureki O
CitationJournal: Science / Year: 2019
Title: Cryo-EM structures capture the transport cycle of the P4-ATPase flippase.
Authors: Masahiro Hiraizumi / Keitaro Yamashita / Tomohiro Nishizawa / Osamu Nureki /
Abstract: In eukaryotic membranes, type IV P-type adenosine triphosphatases (P4-ATPases) mediate the translocation of phospholipids from the outer to the inner leaflet and maintain lipid asymmetry, which is ...In eukaryotic membranes, type IV P-type adenosine triphosphatases (P4-ATPases) mediate the translocation of phospholipids from the outer to the inner leaflet and maintain lipid asymmetry, which is critical for membrane trafficking and signaling pathways. Here, we report the cryo-electron microscopy structures of six distinct intermediates of the human ATP8A1-CDC50a heterocomplex at resolutions of 2.6 to 3.3 angstroms, elucidating the lipid translocation cycle of this P4-ATPase. ATP-dependent phosphorylation induces a large rotational movement of the actuator domain around the phosphorylation site in the phosphorylation domain, accompanied by lateral shifts of the first and second transmembrane helices, thereby allowing phosphatidylserine binding. The phospholipid head group passes through the hydrophilic cleft, while the acyl chain is exposed toward the lipid environment. These findings advance our understanding of the flippase mechanism and the disease-associated mutants of P4-ATPases.
History
DepositionJun 7, 2019-
Header (metadata) releaseAug 28, 2019-
Map releaseAug 28, 2019-
UpdateFeb 10, 2021-
Current statusFeb 10, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.013
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  • Surface view with fitted model
  • Atomic models: PDB-6k7k
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6k7k
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9937.png

Downloads & links

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Map

FileDownload / File: emd_9937.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.013 / Movie #1: 0.013
Minimum - Maximum-0.11616913 - 0.17379658
Average (Standard dev.)0.00023256963 (±0.004262773)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 215.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.830.830.83
M x/y/z260260260
origin x/y/z0.0000.0000.000
length x/y/z215.800215.800215.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS260260260
D min/max/mean-0.1160.1740.000

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Supplemental data

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Mask #1

Fileemd_9937_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_9937_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_9937_half_map_2.map
Projections & Slices
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Sample components

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Entire : ATP8A1-CDC50a

EntireName: ATP8A1-CDC50a
Components
  • Complex: ATP8A1-CDC50a
    • Protein or peptide: Phospholipid-transporting ATPase
    • Protein or peptide: Cell cycle control protein 50A
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: TETRAFLUOROALUMINATE ION
  • Ligand: MAGNESIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: ATP8A1-CDC50a

SupramoleculeName: ATP8A1-CDC50a / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: Expi293F / Recombinant plasmid: pcDNA3.4

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Macromolecule #1: Phospholipid-transporting ATPase

MacromoleculeName: Phospholipid-transporting ATPase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: P-type phospholipid transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130.537852 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GSREFMPTMR RTVSEIRSRA EGYEKTDDVS EKTSLADQEE VRTIFINQPQ LTKFCNNHVS TAKYNIITFL PRFLYSQFRR AANSFFLFI ALLQQIPDVS PTGRYTTLVP LLFILAVAAI KEIIEDIKRH KADNAVNKKQ TQVLRNGAWE IVHWEKVNVG D IVIIKGKE ...String:
GSREFMPTMR RTVSEIRSRA EGYEKTDDVS EKTSLADQEE VRTIFINQPQ LTKFCNNHVS TAKYNIITFL PRFLYSQFRR AANSFFLFI ALLQQIPDVS PTGRYTTLVP LLFILAVAAI KEIIEDIKRH KADNAVNKKQ TQVLRNGAWE IVHWEKVNVG D IVIIKGKE YIPADTVLLS SSEPQAMCYI ETSNLDGETN LKIRQGLPAT SDIKDVDSLM RISGRIECES PNRHLYDFVG NI RLDGHGT VPLGADQILL RGAQLRNTQW VHGIVVYTGH DTKLMQNSTS PPLKLSNVER ITNVQILILF CILIAMSLVC SVG SAIWNR RHSGKDWYLN LNYGGASNFG LNFLTFIILF NNLIPISLLV TLEVVKFTQA YFINWDLDMH YEPTDTAAMA RTSN LNEEL GQVKYIFSDK TGTLTCNVMQ FKKCTIAGVA YGQNSQFGDE KTFSDSSLLE NLQNNHPTAP IICEFLTMMA VCHTA VPER ERDKIIYQAA SPDEGALVRA AKQLNFVFTG RTPDSVIIDS LGQEERYELL NVLEFTSARK RMSVIVRTPS GKLRLY CKG ADTVIYDRLA ETSKYKEITL KHLEQFATEG LRTLCFAVAE ISESDFQEWR AVYQRASTSV QNRLLKLEES YELIEKN LQ LLGATAIEDK LQDQVPETIE TLMKADIKIW ILTGDKQETA INIGHSCKLL KKNMGMIVIN EGSLDGTRET LSRHCTTL G DALRKENDFA LIIDGKTLKY ALTFGVRQYF LDLALSCKAV ICCRVSPLQK SEVVEMVKKQ VKVVTLAIGD GANDVSMIQ TAHVGVGISG NEGLQAANSS DYSIAQFKYL KNLLMIHGAW NYNRVSKCIL YCFYKNIVLY IIEIWFAFVN GFSGQILFER WCIGLYNVM FTAMPPLTLG IFERSCRKEN MLKYPELYKT SQNALDFNTK VFWVHCLNGL FHSVILFWFP LKALQYGTAF G NGKTSDYL LLGNFVYTFV VITVCLKAGL ETSYWTWFSH IAIWGSIALW VVFFGIYSSL WPAIPMAPDM SGEAAMLFSS GV FWMGLLF IPVASLLLDV VYKVIKRTAF KTLVDEVQEL EAKSQDPGAV VLGKSLTERA QLLKNVFKKN HVNLYRSESL QQN LLHGYA FSQDENGIVS QSEVIRAYDT TKQRPDEW

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Macromolecule #2: Cell cycle control protein 50A

MacromoleculeName: Cell cycle control protein 50A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.727527 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAMNYNAKDE VDGGPPCAPG GTAKTRRPDN TAFKQQRLPA WQPILTAGTV LPIFFIIGLI FIPIGIGIFV TSNNIREIEI DYTGTEPSS PCNKCLSPDV TPCFCTINFT LEKSFEGNVF MYYGLSNFYQ NHRRYVKSRD DSQLNGDSSA LLNPSKECEP Y RRNEDKPI ...String:
MAMNYNAKDE VDGGPPCAPG GTAKTRRPDN TAFKQQRLPA WQPILTAGTV LPIFFIIGLI FIPIGIGIFV TSNNIREIEI DYTGTEPSS PCNKCLSPDV TPCFCTINFT LEKSFEGNVF MYYGLSNFYQ NHRRYVKSRD DSQLNGDSSA LLNPSKECEP Y RRNEDKPI APCGAIANSM FNDTLELFLI GNDSYPIPIA LKKKGIAWWT DKNVKFRNPP GGDNLEERFK GTTKPVNWLK PV YMLDSDP DNNGFINEDF IVWMRTAALP TFRKLYRLIE RKSDLHPTLP AGRYSLNVTY NYPVHYFDGR KRMILSTISW MGG KNPFLG IAYIAVGSIS FLLGVVLLVI NHKYRNSSNT ADITI

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Macromolecule #4: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 1 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

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Macromolecule #5: TETRAFLUOROALUMINATE ION

MacromoleculeName: TETRAFLUOROALUMINATE ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: ALF
Molecular weightTheoretical: 102.975 Da
Chemical component information

ChemComp-ALF:
TETRAFLUOROALUMINATE ION

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Macromolecule #6: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #8: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 8 / Number of copies: 1 / 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

Concentration4 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 316665
FSC plot (resolution estimation)

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