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- EMDB-31001: Cryo-EM structure of human ABCA4 in NRPE-bound state -

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Basic information

Entry
Database: EMDB / ID: EMD-31001
TitleCryo-EM structure of human ABCA4 in NRPE-bound state
Map data
Sample
  • Complex: NRPE-bound ABCA4
    • Protein or peptide: Retinal-specific phospholipid-transporting ATPase ABCA4
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
  • 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
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 / phospholipid transporter activity / retinol transmembrane transporter activity / retinal metabolic process / 11-cis retinal binding / 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 / phospholipid transporter activity / retinol transmembrane transporter activity / retinal metabolic process / 11-cis retinal binding / ATPase-coupled intramembrane lipid transporter activity / phototransduction, visible light / phosphatidylethanolamine flippase activity / lipid transporter activity / P-type phospholipid transporter / retinoid binding / 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 / ABC-type transporter activity / photoreceptor outer segment / photoreceptor disc membrane / visual perception / ABC-family proteins mediated transport / transmembrane transport / cytoplasmic vesicle / GTPase activity / intracellular membrane-bounded organelle / ATP hydrolysis activity / endoplasmic reticulum / plasma membrane => GO:0005886 / membrane / ATP binding
Similarity search - Function
Retinal-specific ATP-binding cassette transporter / ABC transporter A / 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: 3.4 Å
AuthorsXie T / Zhang ZK / Gong X
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis of substrate recognition and translocation by human ABCA4.
Authors: Tian Xie / Zike Zhang / Qi Fang / Bowen Du / Xin Gong /
Abstract: Human ATP-binding cassette (ABC) subfamily A (ABCA) transporters mediate the transport of various lipid compounds across the membrane. Mutations in human ABCA transporters have been described to ...Human ATP-binding cassette (ABC) subfamily A (ABCA) transporters mediate the transport of various lipid compounds across the membrane. Mutations in human ABCA transporters have been described to cause severe hereditary disorders associated with impaired lipid transport. However, little is known about the mechanistic details of substrate recognition and translocation by ABCA transporters. Here, we present three cryo-EM structures of human ABCA4, a retina-specific ABCA transporter, in distinct functional states at resolutions of 3.3-3.4 Å. In the nucleotide-free state, the two transmembrane domains (TMDs) exhibit a lateral-opening conformation, allowing the lateral entry of substrate from the lipid bilayer. The N-retinylidene-phosphatidylethanolamine (NRPE), the physiological lipid substrate of ABCA4, is sandwiched between the two TMDs in the luminal leaflet and is further stabilized by an extended loop from extracellular domain 1. In the ATP-bound state, the two TMDs display a closed conformation, which precludes the substrate binding. Our study provides a molecular basis to understand the mechanism of ABCA4-mediated NRPE recognition and translocation, and suggests a common 'lateral access and extrusion' mechanism for ABCA-mediated lipid transport.
History
DepositionFeb 26, 2021-
Header (metadata) releaseJun 30, 2021-
Map releaseJun 30, 2021-
UpdateJul 7, 2021-
Current statusJul 7, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.023
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.023
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7e7o
  • Surface level: 0.023
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_31001.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 280 pix.
= 302.4 Å
1.08 Å/pix.
x 280 pix.
= 302.4 Å
1.08 Å/pix.
x 280 pix.
= 302.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.023 / Movie #1: 0.023
Minimum - Maximum-0.09574973 - 0.17626777
Average (Standard dev.)-2.52673e-05 (±0.0043197735)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 302.40002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z302.400302.400302.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ220220220
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0960.176-0.000

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Supplemental data

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Sample components

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Entire : NRPE-bound ABCA4

EntireName: NRPE-bound ABCA4
Components
  • Complex: NRPE-bound ABCA4
    • Protein or peptide: Retinal-specific phospholipid-transporting ATPase ABCA4
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
  • 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

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Supramolecule #1: NRPE-bound ABCA4

SupramoleculeName: NRPE-bound ABCA4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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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: 261.143547 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADYKDDDDK SGPDEVDASG RMGFVRQIQL LLWKNWTLRK RQKIRFVVEL VWPLSLFLVL IWLRNANPLY SHHECHFPNK AMPSAGMLP WLQGIFCNVN NPCFQSPTPG ESPGIVSNYN NSILARVYRD FQELLMNAPE SQHLGRIWTE LHILSQFMDT L RTHPERIA ...String:
MADYKDDDDK SGPDEVDASG RMGFVRQIQL LLWKNWTLRK RQKIRFVVEL VWPLSLFLVL IWLRNANPLY SHHECHFPNK AMPSAGMLP WLQGIFCNVN NPCFQSPTPG ESPGIVSNYN NSILARVYRD FQELLMNAPE SQHLGRIWTE LHILSQFMDT L RTHPERIA GRGIRIRDIL KDEETLTLFL IKNIGLSDSV VYLLINSQVR PEQFAHGVPD LALKDIACSE ALLERFIIFS QR RGAKTVR YALCSLSQGT LQWIEDTLYA NVDFFKLFRV LPTLLDSRSQ GINLRSWGGI LSDMSPRIQE FIHRPSMQDL LWV TRPLMQ NGGPETFTKL MGILSDLLCG YPEGGGSRVL SFNWYEDNNY KAFLGIDSTR KDPIYSYDRR TTSFCNALIQ SLES NPLTK IAWRAAKPLL MGKILYTPDS PAARRILKNA NSTFEELEHV RKLVKAWEEV GPQIWYFFDN STQMNMIRDT LGNPT VKDF LNRQLGEEGI TAEAILNFLY KGPRESQADD MANFDWRDIF NITDRTLRLV NQYLECLVLD KFESYNDETQ LTQRAL SLL EENMFWAGVV FPDMYPWTSS LPPHVKYKIR MDIDVVEKTN KIKDRYWDSG PRADPVEDFR YIWGGFAYLQ DMVEQGI TR SQVQAEAPVG IYLQQMPYPC FVDDSFMIIL NRCFPIFMVL AWIYSVSMTV KSIVLEKELR LKETLKNQGV SNAVIWCT W FLDSFSIMSM SIFLLTIFIM HGRILHYSDP FILFLFLLAF STATIMLCFL LSTFFSKASL AAACSGVIYF TLYLPHILC FAWQDRMTAE LKKAVSLLSP VAFGFGTEYL VRFEEQGLGL QWSNIGNSPT EGDEFSFLLS MQMMLLDAAV YGLLAWYLDQ VFPGDYGTP LPWYFLLQES YWLGGEGCST REERALEKTE PLTEETEDPE HPEGIHDSFF EREHPGWVPG VCVKNLVKIF E PCGRPAVD RLNITFYENQ ITAFLGHNGA GKTTTLSILT GLLPPTSGTV LVGGRDIETS LDAVRQSLGM CPQHNILFHH LT VAEHMLF YAQLKGKSQE EAQLEMEAML EDTGLHHKRN EEAQDLSGGM QRKLSVAIAF VGDAKVVILD EPTSGVDPYS RRS IWDLLL KYRSGRTIIM STHHMDEADL LGDRIAIIAQ GRLYCSGTPL FLKNCFGTGL YLTLVRKMKN IQSQRKGSEG TCSC SSKGF STTCPAHVDD LTPEQVLDGD VNELMDVVLH HVPEAKLVEC IGQELIFLLP NKNFKHRAYA SLFRELEETL ADLGL SSFG ISDTPLEEIF LKVTEDSDSG PLFAGGAQQK RENVNPRHPC LGPREKAGQT PQDSNVCSPG APAAHPEGQP PPEPEC PGP QLNTGTQLVL QHVQALLVKR FQHTIRSHKD FLAQIVLPAT FVFLALMLSI VIPPFGEYPA LTLHPWIYGQ QYTFFSM DE PGSEQFTVLA DVLLNKPGFG NRCLKEGWLP EYPCGNSTPW KTPSVSPNIT QLFQKQKWTQ VNPSPSCRCS TREKLTML P ECPEGAGGLP PPQRTQRSTE ILQDLTDRNI SDFLVKTYPA LIRSSLKSKF WVNEQRYGGI SIGGKLPVVP ITGEALVGF LSDLGRIMNV SGGPITREAS KEIPDFLKHL ETEDNIKVWF NNKGWHALVS FLNVAHNAIL RASLPKDRSP EEYGITVISQ PLNLTKEQL SEITVLTTSV DAVVAICVIF SMSFVPASFV LYLIQERVNK SKHLQFISGV SPTTYWVTNF LWDIMNYSVS A GLVVGIFI GFQKKAYTSP ENLPALVALL LLYGWAVIPM MYPASFLFDV PSTAYVALSC ANLFIGINSS AITFILELFE NN RTLLRFN AVLRKLLIVF PHFCLGRGLI DLALSQAVTD VYARFGEEHS ANPFHWDLIG KNLFAMVVEG VVYFLLTLLV QRH FFLSQW IAEPTKEPIV DEDDDVAEER QRIITGGNKT DILRLHELTK IYPGTSSPAV DRLCVGVRPG ECFGLLGVNG AGKT TTFKM LTGDTTVTSG DATVAGKSIL TNISEVHQNM GYCPQFDAID ELLTGREHLY LYARLRGVPA EEIEKVANWS IKSLG LTVY ADCLAGTYSG GNKRKLSTAI ALIGCPPLVL LDEPTTGMDP QARRMLWNVI VSIIREGRAV VLTSHSMEEC EALCTR LAI MVKGAFRCMG TIQHLKSKFG DGYIVTMKIK SPKDDLLPDL NPVEQFFQGN FPGSVQRERH YNMLQFQVSS SSLARIF QL LLSHKDSLLI EEYSVTQTTL DQVFVNFAKQ QTESHDLPLH PRAAGASRQA QDLEGSDEVD AVEGSHHHHH HHHHH

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 7 / 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 #4: 1,2-Distearoyl-sn-glycerophosphoethanolamine

MacromoleculeName: 1,2-Distearoyl-sn-glycerophosphoethanolamine / type: ligand / ID: 4 / Number of copies: 3 / Formula: 3PE
Molecular weightTheoretical: 748.065 Da
Chemical component information

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM / Phosphatidylethanolamine

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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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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 184628

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