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- EMDB-25802: The structure of ABCA1 Y482C -

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Basic information

Entry
Database: EMDB / ID: EMD-25802
TitleThe structure of ABCA1 Y482C
Map data
Sample
  • Complex: human ABCA1 with Y482C mutation
    • Protein or peptide: ATP-binding cassette, sub-family A (ABC1), member 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
KeywordsHDL / cholesterol / Tangier Disease / ABC transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


phosphatidylserine floppase activity / phosphatidylcholine floppase activity / phospholipid efflux / ABC-type transporter activity / intracellular membrane-bounded organelle / ATP hydrolysis activity / ATP binding / membrane
Similarity search - Function
ABC transporter A / ABC-2 family transporter protein / ABC-2 type transporter / 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 A (ABC1), member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsSun Y / Li X
Funding support United States, 2 items
OrganizationGrant numberCountry
Damon Runyon Cancer Research FoundationDRR-53S-19 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM135343 United States
CitationJournal: Nat Cardiovasc Res / Year: 2022
Title: Cholesterol efflux mechanism revealed by structural analysis of human ABCA1 conformational states.
Authors: Yingyuan Sun / Xiaochun Li /
Abstract: ATP-binding cassette transporter A1 (ABCA1) utilizes energy derived from ATP hydrolysis to export cholesterol and phospholipids from macrophages. ABCA1 plays a central role in the biosynthesis of ...ATP-binding cassette transporter A1 (ABCA1) utilizes energy derived from ATP hydrolysis to export cholesterol and phospholipids from macrophages. ABCA1 plays a central role in the biosynthesis of high-density lipoprotein (HDL), which mediates reverse cholesterol transport and prevents detrimental lipid deposition. Mutations in ABCA1 cause Tangier disease characterized by a remarkable reduction in the amount of HDL in blood. Here we present cryo-electron microscopy structures of human ABCA1 in ATP-bound and nucleotide-free states. Structural comparison reveals that ATP molecules pull the nucleotide-binding domains together, inducing movements of transmembrane helices 1, 2, 7 and 8 through a series of salt-bridge interactions. Subsequently, extracellular domains (ECDs) undergo a rotation and introduce conformational changes in the ECD-transmembrane interface. In addition, while we observe a sterol-like molecule in ECDs, no such density was observed in the structure of an HDL-deficiency mutant ABCA1, demonstrating the physiological importance of ECDs and a putative interaction mode between ABCA1 and its lipid acceptors. Thus, these structures, along with cholesterol efflux assays, advance the understanding ABCA1-mediated reverse cholesterol transport.
History
DepositionDec 22, 2021-
Header (metadata) releaseJan 26, 2022-
Map releaseJan 26, 2022-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.011
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.011
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7tbz
  • Surface level: 0.011
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25802.png

Downloads & links

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Map

FileDownload / File: emd_25802.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 320 pix.
= 269.44 Å		0.84 Å/pix.
x 320 pix.
= 269.44 Å		0.84 Å/pix.
x 320 pix.
= 269.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.842 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.011 / Movie #1: 0.011
Minimum - Maximum-0.0126723545 - 0.03435047
Average (Standard dev.)0.0002683755 (±0.0015750964)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 269.44 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8420.8420.842
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z269.440269.440269.440
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ380380380
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0130.0340.000

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Supplemental data

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Additional map: Focused reconstruction of ECD

Fileemd_25802_additional_1.map
AnnotationFocused reconstruction of ECD
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_25802_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_25802_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human ABCA1 with Y482C mutation

EntireName: human ABCA1 with Y482C mutation
Components
  • Complex: human ABCA1 with Y482C mutation
    • Protein or peptide: ATP-binding cassette, sub-family A (ABC1), member 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL

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Supramolecule #1: human ABCA1 with Y482C mutation

SupramoleculeName: human ABCA1 with Y482C mutation / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 250 KDa

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Macromolecule #1: ATP-binding cassette, sub-family A (ABC1), member 1

MacromoleculeName: ATP-binding cassette, sub-family A (ABC1), member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 255.594953 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MACWPQLRLL LWKNLTFRRR QTCQLLLEVA WPLFIFLILI SVRLSYPPYE QHECHFPNKA MPSAGTLPWV QGIICNANNP CFRYPTPGE APGVVGNFNK SIVARLFSDA RRLLLYSQKD TSMKDMRKVL RTLQQIKKSS SNLKLQDFLV DNETFSGFLY H NLSLPKST ...String:
MACWPQLRLL LWKNLTFRRR QTCQLLLEVA WPLFIFLILI SVRLSYPPYE QHECHFPNKA MPSAGTLPWV QGIICNANNP CFRYPTPGE APGVVGNFNK SIVARLFSDA RRLLLYSQKD TSMKDMRKVL RTLQQIKKSS SNLKLQDFLV DNETFSGFLY H NLSLPKST VDKMLRADVI LHKVFLQGYQ LHLTSLCNGS KSEEMIQLGD QEVSELCGLP REKLAAAERV LRSNMDILKP IL RTLNSTS PFPSKELAEA TKTLLHSLGT LAQELFSMRS WSDMRQEVMF LTNVNSSSSS TQIYQAVSRI VCGHPEGGGL KIK SLNWYE DNNYKALFGG NGTEEDAETF YDNSTTPYCN DLMKNLESSP LSRIIWKALK PLLVGKILYT PDTPATRQVM AEVN KTFQE LAVFHDLEGM WEELSPKIWT FMENSQEMDL VRMLLDSRDN DHFWEQQLDG LDWTAQDIVA FLAKHPEDVQ SSNGS VCTW REAFNETNQA IRTISRFMEC VNLNKLEPIA TEVWLINKSM ELLDERKFWA GIVFTGITPG SIELPHHVKY KIRMDI DNV ERTNKIKDGY WDPGPRADPF EDMRYVWGGF AYLQDVVEQA IIRVLTGTEK KTGVYMQQMP YPCYVDDIFL RVMSRSM PL FMTLAWIYSV AVIIKGIVYE KEARLKETMR IMGLDNSILW FSWFISSLIP LLVSAGLLVV ILKLGNLLPY SDPSVVFV F LSVFAVVTIL QCFLISTLFS RANLAAACGG IIYFTLYLPY VLCVAWRDYV GFTLKIFASL LSPVAFGFGC EYFALFEEQ GIGVQWDNLF ESPVEEDGFN LTTSVSMMLF DTFLYGVMTW YIEAVFPGQY GIPRPWYFPC TKSYWFGEES DEKSHPGSNQ KRISEICME EEPTHLKLGV SIQNLVKVYR DGMKVAVDGL ALNFYEGQIT SFLGHNGAGK TTTMSILTGL FPPTSGTAYI L GKDIRSEM STIRQNLGVC PQHNVLFDML TVEEHIWFYA RLKGLSEKHV KAEMEQMALD VGLPSSKLKS KTSQLSGGMQ RK LSVALAF VGGSKVVILD EPTAGVDPYS RRGIWELLLK YRQGRTIILS THHMDEADVL GDRIAIISHG KLCCVGSSLF LKN QLGTGY YLTLVKKDVE SSLSSCRNSS STVSYLKKED SVSQSSSDAG LGSDHESDTL TIDVSAISNL IRKHVSEARL VEDI GHELT YVLPYEAAKE GAFVELFHEI DDRLSDLGIS SYGISETTLE EIFLKVAEES GVDAETSDGT LPARRNRRAF GDKQS CLRP FTEDDAADPN DSDIDPESRE TDLLSGMDGK GSYQVKGWKL TQQQFVALLW KRLLIARRSR KGFFAQIVLP AVFVCI ALV FSLIVPPFGK YPSLELQPWM YNEQYTFVSN DAPEDTGTLE LLNALTKDPG FGTRCMEGNP IPDTPCQAGE EEWTTAP VP QTIMDLFQNG NWTMQNPSPA CQCSSDKIKK MLPVCPPGAG GLPPPQRKQN TADILQDLTG RNISDYLVKT YVQIIAKS L KNKIWVNEFR YGGFSLGVSN TQALPPSQEV NDAIKQMKKH LKLAKDSSAD RFLNSLGRFM TGLDTKNNVK VWFNNKGWH AISSFLNVIN NAILRANLQK GENPSHYGIT AFNHPLNLTK QQLSEVALMT TSVDVLVSIC VIFAMSFVPA SFVVFLIQER VSKAKHLQF ISGVKPVIYW LSNFVWDMCN YVVPATLVII IFICFQQKSY VSSTNLPVLA LLLLLYGWSI TPLMYPASFV F KIPSTAYV VLTSVNLFIG INGSVATFVL ELFTDNKLNN INDILKSVFL IFPHFCLGRG LIDMVKNQAM ADALERFGEN RF VSPLSWD LVGRNLFAMA VEGVVFFLIT VLIQYRFFIR PRPVNAKLSP LNDEDEDVRR ERQRILDGGG QNDILEIKEL TKI YRRKRK PAVDRICVGI PPGECFGLLG VNGAGKSSTF KMLTGDTTVT RGDAFLNKNS ILSNIHEVHQ NMGYCPQFDA ITEL LTGRE HVEFFALLRG VPEKEVGKVG EWAIRKLGLV KYGEKYAGNY SGGNKRKLST AMALIGGPPV VFLDEPTTGM DPKAR RFLW NCALSVVKEG RSVVLTSHSM EECEALCTRM AIMVNGRFRC LGSVQHLKNR FGDGYTIVVR IAGSNPDLKP VQDFFG LAF PGSVLKEKHR NMLQYQLPSS LSSLARIFSI LSQSKKRLHI EDYSVSQTTL DQVFVNFAKD QSDDDHLKDL SLHKNQT VV DVAVLTSFLQ DEKVKESYVG DYKDDDDK

UniProtKB: ATP-binding cassette, sub-family A (ABC1), member 1

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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 % / Chamber temperature: 293 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 80072
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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