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- EMDB-65302: Cryo-EM structrure of a human flippase mutant ATP11C Q79E-CDC50A ... -

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Basic information

Entry
Database: EMDB / ID: EMD-65302
TitleCryo-EM structrure of a human flippase mutant ATP11C Q79E-CDC50A in PtdCho-open E2-BeF state
Map data
Sample
  • Complex: ATP11C Q79E-CDC50A lipid flippase complex
    • Protein or peptide: Phospholipid-transporting ATPase IG
    • Protein or peptide: Cell cycle control protein 50A
  • Ligand: MAGNESIUM ION
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsLipid transporter flippase / PC bound E2P BeF state / TRANSPORT PROTEIN
Function / homology
Function and homology information


positive regulation of phospholipid translocation / aminophospholipid flippase activity / aminophospholipid transport / phosphatidylserine flippase activity / protein localization to endosome / phospholipid-translocating ATPase complex / phosphatidylserine floppase activity / positive regulation of protein exit from endoplasmic reticulum / ATPase-coupled intramembrane lipid transporter activity / phosphatidylethanolamine flippase activity ...positive regulation of phospholipid translocation / aminophospholipid flippase activity / aminophospholipid transport / phosphatidylserine flippase activity / protein localization to endosome / phospholipid-translocating ATPase complex / phosphatidylserine floppase activity / positive regulation of protein exit from endoplasmic reticulum / ATPase-coupled intramembrane lipid transporter activity / phosphatidylethanolamine flippase activity / xenobiotic transmembrane transport / P-type phospholipid transporter / phospholipid translocation / azurophil granule membrane / transport vesicle membrane / Ion transport by P-type ATPases / specific granule membrane / positive regulation of neuron projection development / recycling endosome / recycling endosome membrane / late endosome membrane / monoatomic ion transmembrane transport / early endosome membrane / apical plasma membrane / lysosomal membrane / Neutrophil degranulation / endoplasmic reticulum membrane / structural molecule activity / magnesium ion binding / endoplasmic reticulum / Golgi apparatus / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
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 / P-type ATPase, cytoplasmic domain N / P-type ATPase actuator domain / 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 / P-type ATPase, cytoplasmic domain N / P-type ATPase actuator domain / 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 IG / Cell cycle control protein 50A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsQian Y / Abe K
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Science and TechnologyJPMJR22E4 Japan
CitationJournal: J Biol Chem / Year: 2025
Title: Cryo-EM structure of the ATP11C Q79E mutant reveals the structural basis for altered Phospholipid recognition.
Authors: Yuheng Qian / Chai C Gopalasingam / Christoph Gerle / Hideki Shigematsu / Kazuhiro Abe / Atsunori Oshima /
Abstract: Closely related P4-ATPases, ATP11A and ATP11C, act as major phospholipid flippases in the plasma membrane of mammalian cells, with strict substrate specificity for phosphatidylserine (PS) and ...Closely related P4-ATPases, ATP11A and ATP11C, act as major phospholipid flippases in the plasma membrane of mammalian cells, with strict substrate specificity for phosphatidylserine (PS) and phosphatidylethanolamine (PE), but not for phosphatidylcholine (PC), thereby contributing to the asymmetric distribution of PS and PE across bilayers. A previously reported disease-associated Q84E mutation in ATP11A confers the ability to flip PC, implicating the involvement of this conserved residue in substrate specificity. We performed cryo-EM analysis for the equivalent mutant Q79E of ATP11C to address the structural basis for its unusual substrate specificity. Measurement of ATPase activity revealed that the ATP11C Q79E mutant retained PS-dependent activity, whilst gaining robust PC-dependent activity, indicative of expanded substrate specificity, consistent with reported properties in ATP11A Q84E. The cryo-EM structure of ATP11C Q79E mutant in the PC-occluded E2-P state revealed a PC molecule in a reshaped binding pocket. Due to the Q79E mutation and associated conformational changes in its surrounding residues, including Ser91and Asn352, the binding pocket has additional space to accommodate the bulky choline headgroup. Our results provide structural and functional insights into how a single point mutation can alter substrate specificity in a P4-ATPase.
History
DepositionJul 9, 2025-
Header (metadata) releaseNov 26, 2025-
Map releaseNov 26, 2025-
UpdateDec 17, 2025-
Current statusDec 17, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_65302.png

Downloads & links

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Map

FileDownload / File: emd_65302.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 450 pix.
= 338.4 Å		0.75 Å/pix.
x 450 pix.
= 338.4 Å		0.75 Å/pix.
x 450 pix.
= 338.4 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.752 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.9310608 - 3.043623
Average (Standard dev.)-0.0023873523 (±0.061378997)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 338.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_65302_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_65302_half_map_2.map
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Histogram (log scale)

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Sample components

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Entire : ATP11C Q79E-CDC50A lipid flippase complex

EntireName: ATP11C Q79E-CDC50A lipid flippase complex
Components
  • Complex: ATP11C Q79E-CDC50A lipid flippase complex
    • Protein or peptide: Phospholipid-transporting ATPase IG
    • Protein or peptide: Cell cycle control protein 50A
  • Ligand: MAGNESIUM ION
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: ATP11C Q79E-CDC50A lipid flippase complex

SupramoleculeName: ATP11C Q79E-CDC50A lipid flippase complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 170 kDa/nm

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Macromolecule #1: Phospholipid-transporting ATPase IG

MacromoleculeName: Phospholipid-transporting ATPase IG / 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: 124.165258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CAGEEKRVGT RTVFVGNHPV SETEAYIAQR FCDNRIVSSK YTLWNFLPKN LFEQFRRIAN FYFLIIFLVE VTVDTPTSPV TSGLPLFFV ITVTAIKQGY EDWLRHRADN EVNKSTVYII ENAKRVRKES EKIKVGDVVE VQADETFPCD LILLSSCTTD G TCYVTTAS ...String:
CAGEEKRVGT RTVFVGNHPV SETEAYIAQR FCDNRIVSSK YTLWNFLPKN LFEQFRRIAN FYFLIIFLVE VTVDTPTSPV TSGLPLFFV ITVTAIKQGY EDWLRHRADN EVNKSTVYII ENAKRVRKES EKIKVGDVVE VQADETFPCD LILLSSCTTD G TCYVTTAS LDGESNCKTH YAVRDTIALC TAESIDTLRA AIECEQPQPD LYKFVGRINI YSNSLEAVAR SLGPENLLLK GA TLKNTEK IYGVAVYTGM ETKMALNYQG KSQKRSAVEK SINAFLIVYL FILLTKAAVC TTLKYVWQST PYNDEPWYNQ KTQ KERETL KVLKMFTDFL SFMVLFNFII PVSMYVTVEM QKFLGSFFIS WDKDFYDEEI NEGALVNTSD LNEELGQVDY VFT (BFD)KTGTL TENSMEFIEC CIDGHKYKGV TQEVDGLSQT DGTLTYFDKV DKNREELFLR ALCLCHTVEI KTNDAVDGAT ESAELTYIS SSPDEIALVK GAKRYGFTFL GNRNGYMRVE NQRKEIEEYE LLHTLNFDAV RRRMSVIVKT QEGDILLFCK G ADSAVFPR VQNHEIELTK VHVERNAMDG YRTLCVAFKE IAPDDYERIN RQLIEAKMAL QDREEKMEKV FDDIETNMNL IG ATAVEDK LQDQAAETIE ALHAAGLKVW VLTGDKMETA KSTCYACRLF QTNTELLELT TKTIEESERK EDRLHELLIE YRK KLLHEF PKSTRSFKKA WTEHQEYGLI IDGSTLSLIL NSSQDSSSNN YKSIFLQICM KCTAVLCCRM APLQKAQIVR MVKN LKGSP ITLSIGDGAN DVSMILESHV GIGIKGKEGR QAARNSDYSV PKFKHLKKLL LAHGHLYYVR IAHLVQYFFY KNLCF ILPQ FLYQFFCGFS QQPLYDAAYL TMYNICFTSL PILAYSLLEQ HINIDTLTSD PRLYMKISGN AMLQLGPFLY WTFLAA FEG TVFFFGTYFL FQTASLEENG KVYGNWTFGT IVFTVLVFTV TLKLALDTRF WTWINHFVIW GSLAFYVFFS FFWGGII WP FLKQQRMYFV FAQMLSSVST WLAIILLIFI SLFPEILLIV LKNVR

UniProtKB: Phospholipid-transporting ATPase IG

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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: 40.900801 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 APCGAIMNSM FNDTLELFLI GQDSYPIPIA LKKKGIAWWT DKNVKFRNPP GGDNLEERFK GTTKPVNWLK PV YMLDSDP DNNGFINEDF IVWMRTAALP TFRKLYRLIE RKSDLHPTLP AGRYWLNVTY NYPVHYFDGR KRMILSTISW MGG KNPFLG IAYIAVGSIS FLLGVVLLVI NHKYRNSSNT ADITI

UniProtKB: Cell cycle control protein 50A

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / 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

Concentration6 mg/mL
BufferpH: 6.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER/RHODIUM / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
Details: Glow discharge was performed on both sides of the grid
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Specialist opticsEnergy filter - Name: In-column Omega Filter / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 8950 / Average electron dose: 60.0 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: 1.6 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 60000
Sample stageSpecimen holder model: JEOL CRYOSPECPORTER / Cooling holder cryogen: NITROGEN

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Image processing

DetailsImages were collected using CDS mode
CTF correctionSoftware - Name: cryoSPARC (ver. 4.4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio reconstruction using cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 69202
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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