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- PDB-7e7q: Cryo-EM structure of human ABCA4 in ATP-bound state -

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Basic information

Entry
Database: PDB / ID: 7e7q
TitleCryo-EM structure of human ABCA4 in ATP-bound state
ComponentsRetinal-specific phospholipid-transporting ATPase ABCA4
KeywordsTRANSLOCASE / lipid transport / MEMBRANE PROTEIN
Function / homology
Function and homology information


N-retinylidene-phosphatidylethanolamine flippase activity / flippase activity / rod photoreceptor disc membrane / 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 ...N-retinylidene-phosphatidylethanolamine flippase activity / flippase activity / rod photoreceptor disc membrane / 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 / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporter-like, ATP-binding domain / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / Retinal-specific phospholipid-transporting ATPase ABCA4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsXie, T. / Zhang, Z.K. / 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, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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Structure visualization

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Assembly

Deposited unit
A: Retinal-specific phospholipid-transporting ATPase ABCA4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)265,57514
Polymers261,1421
Non-polymers4,43313
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5880 Å2
ΔGint21 kcal/mol
Surface area93330 Å2

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Components

#1: Protein Retinal-specific phospholipid-transporting ATPase ABCA4 / ATP-binding cassette sub-family A member 4 / RIM ABC transporter / RIM protein / RmP / Retinal- ...ATP-binding cassette sub-family A member 4 / RIM ABC transporter / RIM protein / RmP / Retinal-specific ATP-binding cassette transporter / Stargardt disease protein


Mass: 261141.578 Da / Num. of mol.: 1 / Mutation: E1087Q,E2096Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCA4, ABCR / Production host: Homo sapiens (human)
References: UniProt: P78363, P-type phospholipid transporter
#2: Polysaccharide beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3[DManpb1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2-2-2/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ATP-bound ABCA4 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.1_3865: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173278 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01115636
ELECTRON MICROSCOPYf_angle_d0.95421287
ELECTRON MICROSCOPYf_dihedral_angle_d28.0032244
ELECTRON MICROSCOPYf_chiral_restr0.0612479
ELECTRON MICROSCOPYf_plane_restr0.0062676

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