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- PDB-7w01: Cryo-EM structure of nucleotide-free ABCA3 -

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Basic information

Entry
Database: PDB / ID: 7w01
TitleCryo-EM structure of nucleotide-free ABCA3
ComponentsPhospholipid-transporting ATPase ABCA3
KeywordsTRANSLOCASE / ABC transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


lamellar body membrane / Defective ABCA3 causes SMDP3 / Defective ABCA3 causes SMDP3 / alveolar lamellar body membrane / positive regulation of protein homooligomerization / regulation of phosphatidylcholine metabolic process / phosphatidylcholine transfer activity / lamellar body / positive regulation of phospholipid transport / xenobiotic export from cell ...lamellar body membrane / Defective ABCA3 causes SMDP3 / Defective ABCA3 causes SMDP3 / alveolar lamellar body membrane / positive regulation of protein homooligomerization / regulation of phosphatidylcholine metabolic process / phosphatidylcholine transfer activity / lamellar body / positive regulation of phospholipid transport / xenobiotic export from cell / alveolar lamellar body / organelle assembly / phosphatidylcholine flippase activity / positive regulation of phospholipid efflux / lipid transporter activity / ABC transporters in lipid homeostasis / phosphatidylglycerol metabolic process / regulation of lipid biosynthetic process / phosphatidylcholine metabolic process / xenobiotic transmembrane transport / phospholipid homeostasis / Surfactant metabolism / multivesicular body membrane / phospholipid transport / ABC-type xenobiotic transporter / protein metabolic process / surfactant homeostasis / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / xenobiotic transport / lipid transport / positive regulation of cholesterol efflux / ATPase-coupled transmembrane transporter activity / response to glucocorticoid / lung development / cytoplasmic vesicle membrane / late endosome / membrane => GO:0016020 / response to xenobiotic stimulus / lysosomal membrane / intracellular membrane-bounded organelle / ATP hydrolysis activity / extracellular space / ATP binding / plasma membrane
Similarity search - Function
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
Chem-POV / 1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Phospholipid-transporting ATPase ABCA3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsXie, T. / Zhang, Z.K. / Yue, J. / Gong, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Adv / Year: 2022
Title: Cryo-EM structures of the human surfactant lipid transporter ABCA3.
Authors: Tian Xie / Zike Zhang / Jian Yue / Qi Fang / Xin Gong /
Abstract: The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter ABCA3 plays a critical role in pulmonary surfactant biogenesis. Mutations in human ABCA3 have been recognized as the most ...The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter ABCA3 plays a critical role in pulmonary surfactant biogenesis. Mutations in human ABCA3 have been recognized as the most frequent causes of inherited surfactant dysfunction disorders. Despite two decades of research, in vitro biochemical and structural studies of ABCA3 are still lacking. Here, we report the cryo-EM structures of human ABCA3 in two distinct conformations, both at resolution of 3.3 Å. In the absence of ATP, ABCA3 adopts a "lateral-opening" conformation with the lateral surfaces of transmembrane domains (TMDs) exposed to the membrane and features two positively charged cavities within the TMDs as potential substrate binding sites. ATP binding induces pronounced conformational changes, resulting in the collapse of the potential substrate binding cavities. Our results help to rationalize the disease-causing mutations in human ABCA3 and suggest a conserved "lateral access and extrusion" mechanism for both lipid export and import mediated by ABCA transporters.
History
DepositionNov 17, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phospholipid-transporting ATPase ABCA3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)200,5948
Polymers196,5141
Non-polymers4,0817
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Phospholipid-transporting ATPase ABCA3 / ABC-C transporter / ATP-binding cassette sub-family A member 3 / ATP-binding cassette transporter 3 ...ABC-C transporter / ATP-binding cassette sub-family A member 3 / ATP-binding cassette transporter 3 / ATP-binding cassette 3 / Xenobiotic-transporting ATPase ABCA3


Mass: 196513.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCA3, ABC3 / Production host: Homo sapiens (human)
References: UniProt: Q99758, P-type phospholipid transporter, ABC-type xenobiotic transporter
#2: 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.: 2 / Source method: obtained synthetically / 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
#3: Chemical ChemComp-PX4 / 1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Dimyristoylphosphatidylcholine


Mass: 678.940 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H73NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: DMPC, phospholipid*YM
#4: Chemical ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC / POPC


Mass: 760.076 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C42H82NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
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: ABCA3 / 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 / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
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: 111435 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01113360
ELECTRON MICROSCOPYf_angle_d1.06318163
ELECTRON MICROSCOPYf_dihedral_angle_d24.4162624
ELECTRON MICROSCOPYf_chiral_restr0.062081
ELECTRON MICROSCOPYf_plane_restr0.0062243

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