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- EMDB-23618: Human ABCA4 structure in complex with N-ret-PE -

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Basic information

Entry
Database: EMDB / ID: EMD-23618
TitleHuman ABCA4 structure in complex with N-ret-PE
Map data
Sample
  • Complex: ABCA4 structure in complex with N-ret-PE
    • Protein or peptide: Retinal-specific phospholipid-transporting ATPase ABCA4
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2S)-3-[2-[(E)-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenylidene]amino]ethoxy-oxidanyl-phosphoryl]oxy-2-[(Z)-octadec-9-enoyl]oxy-propyl] (Z)-octadec-9-enoate
  • Ligand: MAGNESIUM ION
Function / homology
Function and homology information


rod photoreceptor disc membrane / flippase activity / N-retinylidene-phosphatidylethanolamine flippase activity / all-trans retinal binding / phospholipid transfer to membrane / retinol transmembrane transporter activity / phospholipid transporter activity / 11-cis retinal binding / retinal metabolic process / ATPase-coupled intramembrane lipid transporter activity ...rod photoreceptor disc membrane / flippase activity / N-retinylidene-phosphatidylethanolamine flippase activity / all-trans retinal binding / phospholipid transfer to membrane / retinol transmembrane transporter activity / phospholipid transporter activity / 11-cis retinal binding / retinal metabolic process / ATPase-coupled intramembrane lipid transporter activity / phosphatidylethanolamine flippase activity / phototransduction, visible light / retinoid binding / P-type phospholipid transporter / photoreceptor cell maintenance / phospholipid translocation / retinoid metabolic process / lipid transport / Retinoid cycle disease events / The canonical retinoid cycle in rods (twilight vision) / ATPase-coupled transmembrane transporter activity / photoreceptor outer segment / ABC-type transporter activity / visual perception / ABC-family proteins mediated transport / transmembrane transport / photoreceptor disc membrane / cytoplasmic vesicle / intracellular membrane-bounded organelle / GTPase activity / endoplasmic reticulum / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
Similarity search - Function
Retinal-specific ATP-binding cassette transporter / ABC-2 family transporter protein / ABC transporter A / 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 ...Retinal-specific ATP-binding cassette transporter / ABC-2 family transporter protein / ABC transporter A / 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
Retinal-specific phospholipid-transporting ATPase ABCA4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsScortecci JF / Van Petegem F / Molday RS
Funding support Canada, 1 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease.
Authors: Jessica Fernandes Scortecci / Laurie L Molday / Susan B Curtis / Fabian A Garces / Pankaj Panwar / Filip Van Petegem / Robert S Molday /
Abstract: ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function ...ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function mutations cause Stargardt disease (STGD1), a macular dystrophy associated with severe vision loss. To define the mechanisms underlying substrate binding and STGD1, we determine the cryo-EM structure of ABCA4 in its substrate-free and bound states. The two structures are similar and delineate an elongated protein with the two transmembrane domains (TMD) forming an outward facing conformation, extended and twisted exocytoplasmic domains (ECD), and closely opposed nucleotide binding domains. N-Ret-PE is wedged between the two TMDs and a loop from ECD1 within the lumen leaflet consistent with a lateral access mechanism and is stabilized through hydrophobic and ionic interactions with residues from the TMDs and ECDs. Our studies provide a framework for further elucidating the molecular mechanism associated with lipid transport and disease and developing promising disease interventions.
History
DepositionMar 14, 2021-
Header (metadata) releaseSep 8, 2021-
Map releaseSep 8, 2021-
UpdateOct 20, 2021-
Current statusOct 20, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.051
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.051
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7m1q
  • Surface level: 0.051
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23618.png

Downloads & links

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Map

FileDownload / File: emd_23618.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.77219 Å
Density
Contour LevelBy AUTHOR: 0.051 / Movie #1: 0.051
Minimum - Maximum-0.12378565 - 0.42859513
Average (Standard dev.)0.00025796192 (±0.007805096)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 370.65002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.77218750.77218750.7721875
M x/y/z480480480
origin x/y/z0.0000.0000.000
length x/y/z370.650370.650370.650
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS480480480
D min/max/mean-0.1240.4290.000

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Supplemental data

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Sample components

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Entire : ABCA4 structure in complex with N-ret-PE

EntireName: ABCA4 structure in complex with N-ret-PE
Components
  • Complex: ABCA4 structure in complex with N-ret-PE
    • Protein or peptide: Retinal-specific phospholipid-transporting ATPase ABCA4
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2S)-3-[2-[(E)-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenylidene]amino]ethoxy-oxidanyl-phosphoryl]oxy-2-[(Z)-octadec-9-enoyl]oxy-propyl] (Z)-octadec-9-enoate
  • Ligand: MAGNESIUM ION

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Supramolecule #1: ABCA4 structure in complex with N-ret-PE

SupramoleculeName: ABCA4 structure in complex with N-ret-PE / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Recombinantly expressed human ABCA4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 250 KDa

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Macromolecule #1: Retinal-specific phospholipid-transporting ATPase ABCA4

MacromoleculeName: Retinal-specific phospholipid-transporting ATPase ABCA4
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: 256.202531 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA MPSAGMLPWL QGIFCNVNNP CFQSPTPGE SPGIVSNYNN SILARVYRDF QELLMNAPES QHLGRIWTEL HILSQFMDTL RTHPERIAGR GIRIRDILKD E ETLTLFLI ...String:
MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA MPSAGMLPWL QGIFCNVNNP CFQSPTPGE SPGIVSNYNN SILARVYRDF QELLMNAPES QHLGRIWTEL HILSQFMDTL RTHPERIAGR GIRIRDILKD E ETLTLFLI KNIGLSDSVV YLLINSQVRP EQFAHGVPDL ALKDIACSEA LLERFIIFSQ RRGAKTVRYA LCSLSQGTLQ WI EDTLYAN VDFFKLFRVL PTLLDSRSQG INLRSWGGIL SDMSPRIQEF IHRPSMQDLL WVTRPLMQNG GPETFTKLMG ILS DLLCGY PEGGGSRVLS FNWYEDNNYK AFLGIDSTRK DPIYSYDRRT TSFCNALIQS LESNPLTKIA WRAAKPLLMG KILY TPDSP AARRILKNAN STFEELEHVR KLVKAWEEVG PQIWYFFDNS TQMNMIRDTL GNPTVKDFLN RQLGEEGITA EAILN FLYK GPRESQADDM ANFDWRDIFN ITDRTLRLVN QYLECLVLDK FESYNDETQL TQRALSLLEE NMFWAGVVFP DMYPWT SSL PPHVKYKIRM DIDVVEKTNK IKDRYWDSGP RADPVEDFRY IWGGFAYLQD MVEQGITRSQ VQAEAPVGIY LQQMPYP CF VDDSFMIILN RCFPIFMVLA WIYSVSMTVK SIVLEKELRL KETLKNQGVS NAVIWCTWFL DSFSIMSMSI FLLTIFIM H GRILHYSDPF ILFLFLLAFS TATIMLCFLL STFFSKASLA AACSGVIYFT LYLPHILCFA WQDRMTAELK KAVSLLSPV AFGFGTEYLV RFEEQGLGLQ WSNIGNSPTE GDEFSFLLSM QMMLLDAAVY GLLAWYLDQV FPGDYGTPLP WYFLLQESYW LGGEGCSTR EERALEKTEP LTEETEDPEH PEGIHDSFFE REHPGWVPGV CVKNLVKIFE PCGRPAVDRL NITFYENQIT A FLGHNGAG KTTTLSILTG LLPPTSGTVL VGGRDIETSL DAVRQSLGMC PQHNILFHHL TVAEHMLFYA QLKGKSQEEA QL EMEAMLE DTGLHHKRNE EAQDLSGGMQ RKLSVAIAFV GDAKVVILDE PTSGVDPYSR RSIWDLLLKY RSGRTIIMST HHM DEADLL GDRIAIIAQG RLYCSGTPLF LKNCFGTGLY LTLVRKMKNI QSQRKGSEGT CSCSSKGFST TCPAHVDDLT PEQV LDGDV NELMDVVLHH VPEAKLVECI GQELIFLLPN KNFKHRAYAS LFRELEETLA DLGLSSFGIS DTPLEEIFLK VTEDS DSGP LFAGGAQQKR ENVNPRHPCL GPREKAGQTP QDSNVCSPGA PAAHPEGQPP PEPECPGPQL NTGTQLVLQH VQALLV KRF QHTIRSHKDF LAQIVLPATF VFLALMLSIV IPPFGEYPAL TLHPWIYGQQ YTFFSMDEPG SEQFTVLADV LLNKPGF GN RCLKEGWLPE YPCGNSTPWK TPSVSPNITQ LFQKQKWTQV NPSPSCRCST REKLTMLPEC PEGAGGLPPP QRTQRSTE I LQDLTDRNIS DFLVKTYPAL IRSSLKSKFW VNEQRYGGIS IGGKLPVVPI TGEALVGFLS DLGRIMNVSG GPITREASK EIPDFLKHLE TEDNIKVWFN NKGWHALVSF LNVAHNAILR ASLPKDRSPE EYGITVISQP LNLTKEQLSE ITVLTTSVDA VVAICVIFS MSFVPASFVL YLIQERVNKS KHLQFISGVS PTTYWVTNFL WDIMNYSVSA GLVVGIFIGF QKKAYTSPEN L PALVALLL LYGWAVIPMM YPASFLFDVP STAYVALSCA NLFIGINSSA ITFILELFEN NRTLLRFNAV LRKLLIVFPH FC LGRGLID LALSQAVTDV YARFGEEHSA NPFHWDLIGK NLFAMVVEGV VYFLLTLLVQ RHFFLSQWIA EPTKEPIVDE DDD VAEERQ RIITGGNKTD ILRLHELTKI YPGTSSPAVD RLCVGVRPGE CFGLLGVNGA GKTTTFKMLT GDTTVTSGDA TVAG KSILT NISEVHQNMG YCPQFDAIDE LLTGREHLYL YARLRGVPAE EIEKVANWSI KSLGLTVYAD CLAGTYSGGN KRKLS TAIA LIGCPPLVLL DEPTTGMDPQ ARRMLWNVIV SIIREGRAVV LTSHSMEECE ALCTRLAIMV KGAFRCMGTI QHLKSK FGD GYIVTMKIKS PKDDLLPDLN PVEQFFQGNF PGSVQRERHY NMLQFQVSSS SLARIFQLLL SHKDSLLIEE YSVTQTT LD QVFVNFAKQQ TESHDLPLHP RAAGASRQAQ D

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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: 6 / 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 #5: [(2S)-3-[2-[(E)-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyc...

MacromoleculeName: [(2S)-3-[2-[(E)-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenylidene]amino]ethoxy-oxidanyl-phosphoryl]oxy-2-[(Z)-octadec-9-enoyl]oxy-propyl] (Z)-octadec-9-enoate
type: ligand / ID: 5 / Number of copies: 1 / Formula: HZL
Molecular weightTheoretical: 1.010454 KDa
Chemical component information

ChemComp-HZL:
[(2S)-3-[2-[(E)-[(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenylidene]amino]ethoxy-oxidanyl-phosphoryl]oxy-2-[(Z)-octadec-9-enoyl]oxy-propyl] (Z)-octadec-9-enoate

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Macromolecule #6: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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: 7.4
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300
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: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 739898
CTF correctionSoftware - Name: cryoSPARC (ver. 2.9)
Startup modelType of model: OTHER / Details: Ab initio reconstruction
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 209790
FSC plot (resolution estimation)

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