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- EMDB-31971: Cryo-EM structure of the human P4-type flippase ATP8B1-CDC50A in ... -

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Basic information

Entry
Database: EMDB / ID: EMD-31971
TitleCryo-EM structure of the human P4-type flippase ATP8B1-CDC50A in the auto-inhibited E2Pi-PS state
Map data
Sample
  • Complex: ATP8B1-CDC50A complex
    • Protein or peptide: Phospholipid-transporting ATPase IC
    • Protein or peptide: Cell cycle control protein 50A
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
Function / homology
Function and homology information


vestibulocochlear nerve formation / regulation of plasma membrane organization / regulation of microvillus assembly / positive regulation of phospholipid translocation / phosphatidylcholine flippase activity / aminophospholipid flippase activity / aminophospholipid transport / phosphatidylserine flippase activity / protein localization to endosome / inner ear receptor cell development ...vestibulocochlear nerve formation / regulation of plasma membrane organization / regulation of microvillus assembly / positive regulation of phospholipid translocation / phosphatidylcholine flippase activity / aminophospholipid flippase activity / aminophospholipid transport / phosphatidylserine flippase activity / protein localization to endosome / inner ear receptor cell development / phospholipid-translocating ATPase complex / ATPase-coupled intramembrane lipid transporter activity / phosphatidylserine floppase activity / positive regulation of protein exit from endoplasmic reticulum / cardiolipin binding / xenobiotic transmembrane transport / apical protein localization / phosphatidylcholine floppase activity / stereocilium / bile acid metabolic process / P-type phospholipid transporter / bile acid and bile salt transport / phospholipid translocation / transport vesicle membrane / azurophil granule membrane / Golgi organization / Ion transport by P-type ATPases / specific granule membrane / monoatomic ion transmembrane transport / regulation of chloride transport / sensory perception of sound / trans-Golgi network / positive regulation of neuron projection development / late endosome membrane / early endosome membrane / nuclear body / apical plasma membrane / negative regulation of DNA-templated transcription / Neutrophil degranulation / structural molecule activity / Golgi apparatus / magnesium ion binding / endoplasmic reticulum / ATP hydrolysis activity / nucleoplasm / 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 IC / Cell cycle control protein 50A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.98 Å
AuthorsChen MT / Chen Y / Chen ZP / Zhou CZ / Hou WT
Funding support China, 2 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2019YFA0508500 China
Chinese Academy of SciencesXDB37020202 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding.
Authors: Meng-Ting Cheng / Yu Chen / Zhi-Peng Chen / Xin Liu / Zhiyong Zhang / Yuxing Chen / Wen-Tao Hou / Cong-Zhao Zhou /
Abstract: SignificanceATP8B1 is a P4 ATPase that maintains membrane asymmetry by transporting phospholipids across the cell membrane. Disturbance of lipid asymmetry will lead to the imbalance of the cell ...SignificanceATP8B1 is a P4 ATPase that maintains membrane asymmetry by transporting phospholipids across the cell membrane. Disturbance of lipid asymmetry will lead to the imbalance of the cell membrane and eventually, cell death. Thus, defects in ATP8B1 are usually associated with severe human diseases, such as intrahepatic cholestasis. The present structures of ATP8B1 complexed with its auxiliary noncatalytic partners CDC50A and CDC50B reveal an autoinhibited state of ATP8B1 that could be released upon substrate binding. Moreover, release of this autoinhibition could be facilitated by the bile acids, which are key factors that alter the membrane asymmetry of hepatocytes. This enabled us to figure out a feedback loop of bile acids and lipids across the cell membrane.
History
DepositionSep 16, 2021-
Header (metadata) releaseMar 30, 2022-
Map releaseMar 30, 2022-
UpdateOct 12, 2022-
Current statusOct 12, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_31971.png

Downloads & links

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Map

FileDownload / File: emd_31971.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.013 Å
Density
Contour LevelBy AUTHOR: 0.0098
Minimum - Maximum-0.030951126 - 0.055630594
Average (Standard dev.)0.00017697785 (±0.0023978557)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 243.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : ATP8B1-CDC50A complex

EntireName: ATP8B1-CDC50A complex
Components
  • Complex: ATP8B1-CDC50A complex
    • Protein or peptide: Phospholipid-transporting ATPase IC
    • Protein or peptide: Cell cycle control protein 50A
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

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Supramolecule #1: ATP8B1-CDC50A complex

SupramoleculeName: ATP8B1-CDC50A complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Phospholipid-transporting ATPase IC

MacromoleculeName: Phospholipid-transporting ATPase IC / 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: 148.458562 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMSTERDS ETTFDEDSQP NDEVVPYSDD ETEDELDDQG SAVEPEQNR VNREAEENRE PFRKECTWQV KANDRKYHEQ PHFMNTKFLC IKESKYANNA IKTYKYNAFT FIPMNLFEQF K RAANLYFL ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTMSTERDS ETTFDEDSQP NDEVVPYSDD ETEDELDDQG SAVEPEQNR VNREAEENRE PFRKECTWQV KANDRKYHEQ PHFMNTKFLC IKESKYANNA IKTYKYNAFT FIPMNLFEQF K RAANLYFL ALLILQAVPQ ISTLAWYTTL VPLLVVLGVT AIKDLVDDVA RHKMDKEINN RTCEVIKDGR FKVAKWKEIQ VG DVIRLKK NDFVPADILL LSSSEPNSLC YVETAELDGE TNLKFKMSLE ITDQYLQRED TLATFDGFIE CEEPNNRLDK FTG TLFWRN TSFPLDADKI LLRGCVIRNT DFCHGLVIFA GADTKIMKNS GKTRFKRTKI DYLMNYMVYT IFVVLILLSA GLAI GHAYW EAQVGNSSWY LYDGEDDTPS YRGFLIFWGY IIVLNTMVPI SLYVSVEVIR LGQSHFINWD LQMYYAEKDT PAKAR TTTL NEQLGQIHYI FSDKTGTLTQ NIMTFKKCCI NGQIYGDHRD ASQHNHNKIE QVDFSWNTYA DGKLAFYDHY LIEQIQ SGK EPEVRQFFFL LAVCHTVMVD RTDGQLNYQA ASPDEGALVN AARNFGFAFL ARTQNTITIS ELGTERTYNV LAILDFN SD RKRMSIIVRT PEGNIKLYCK GADTVIYERL HRMNPTKQET QDALDIFANE TLRTLCLCYK EIEEKEFTEW NKKFMAAS V ASTNRDEALD KVYEEIEKDL ILLGATAIED KLQDGVPETI SKLAKADIKI WVLTGDKKET AENIGFACEL LTEDTTICY GEDINSLLHA RMENQRNRGG VYAKFAPPVQ ESFFPPGGNR ALIITGSWLN EILLEKKTKR NKILKLKFPR TEEERRMRTQ SKRRLEAKK EQRQKNFVDL ACECSAVICC RVTPKQKAMV VDLVKRYKKA ITLAIGDGAN DVNMIKTAHI GVGISGQEGM Q AVMSSDYS FAQFRYLQRL LLVHGRWSYI RMCKFLRYFF YKNFAFTLVH FWYSFFNGYS AQTAYEDWFI TLYNVLYTSL PV LLMGLLD QDVSDKLSLR FPGLYIVGQR DLLFNYKRFF VSLLHGVLTS MILFFIPLGA YLQTVGQDGE APSDYQSFAV TIA SALVIT VNFQIGLDTS YWTFVNAFSI FGSIALYFGI MFDFHSAGIH VLFPSAFQFT GTASNALRQP YIWLTIILAV AVCL LPVVA IRFLSMTIWP SESDKIQKHR KRLKAEEQWQ RRQQVFRRGV STRRSAYAFS HQRGYADLIS SGRSIRKKRS PLDAI VADG TAEYRRTGDS

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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: 41.845746 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASMAMNYNA KDEVDGGPPC APGGTAKTRR PDNTAFKQQR LPAWQPILTA GTVLPIFFII GLIFIPIGIG IFVTSNNIRE IEIDYTGTE PSSPCNKCLS PDVTPCFCTI NFTLEKSFEG NVFMYYGLSN FYQNHRRYVK SRDDSQLNGD SSALLNPSKE C EPYRRNED ...String:
MASMAMNYNA KDEVDGGPPC APGGTAKTRR PDNTAFKQQR LPAWQPILTA GTVLPIFFII GLIFIPIGIG IFVTSNNIRE IEIDYTGTE PSSPCNKCLS PDVTPCFCTI NFTLEKSFEG NVFMYYGLSN FYQNHRRYVK SRDDSQLNGD SSALLNPSKE C EPYRRNED KPIAPCGAIA NSMFNDTLEL FLIGNDSYPI PIALKKKGIA WWTDKNVKFR NPPGGDNLEE RFKGTTKPVN WL KPVYMLD SDPDNNGFIN EDFIVWMRTA ALPTFRKLYR LIERKSDLHP TLPAGRYSLN VTYNYPVHYF DGRKRMILST ISW MGGKNP FLGIAYIAVG SISFLLGVVL LVINHKYRNS SNTADITIHH HHHH

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Macromolecule #3: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...

MacromoleculeName: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
type: ligand / ID: 3 / Number of copies: 1 / Formula: P5S
Molecular weightTheoretical: 792.075 Da
Chemical component information

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

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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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: LAB6
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.98 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Number images used: 160435
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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