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- EMDB-32224: Cryo-EM structure of C22:0-CoA bound human very long-chain fatty ... -

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Basic information

Entry
Database: EMDB / ID: EMD-32224
TitleCryo-EM structure of C22:0-CoA bound human very long-chain fatty acid ABC transporter ABCD1
Map data
Sample
  • Organelle or cellular component: human peroxisomal ABCD1
    • Protein or peptide: Peroxisomal Membrane Protein related,ATP-binding cassette sub-family D member 1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethyl] docosanethioate
Keywordsvery long-chain fatty / Peroxisome / ABC transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


ABC transporters in lipid homeostasis / Linoleic acid (LA) metabolism / alpha-linolenic acid (ALA) metabolism / Beta-oxidation of very long chain fatty acids / Class I peroxisomal membrane protein import / ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / very long-chain fatty acyl-CoA hydrolase activity / positive regulation of unsaturated fatty acid biosynthetic process ...ABC transporters in lipid homeostasis / Linoleic acid (LA) metabolism / alpha-linolenic acid (ALA) metabolism / Beta-oxidation of very long chain fatty acids / Class I peroxisomal membrane protein import / ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / very long-chain fatty acyl-CoA hydrolase activity / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / alpha-linolenic acid metabolic process / long-chain fatty acid catabolic process / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / alpha-linolenic acid (ALA) metabolism / regulation of fatty acid beta-oxidation / Beta-oxidation of very long chain fatty acids / Class I peroxisomal membrane protein import / very long-chain fatty acid metabolic process / sterol homeostasis / peroxisome organization / regulation of mitochondrial depolarization / ABC transporters in lipid homeostasis / myelin maintenance / fatty acyl-CoA hydrolase activity / regulation of cellular response to oxidative stress / Hydrolases; Acting on ester bonds; Thioester hydrolases / positive regulation of fatty acid beta-oxidation / linoleic acid metabolic process / regulation of oxidative phosphorylation / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / fatty acid elongation / peroxisomal membrane / long-chain fatty acid transmembrane transporter activity / fatty acid beta-oxidation / ATPase-coupled transmembrane transporter activity / negative regulation of cytokine production involved in inflammatory response / fatty acid homeostasis / ABC-type transporter activity / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / mitochondrial membrane / ADP binding / peroxisome / protein heterodimerization activity / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / protein homodimerization activity / ATP hydrolysis activity / ATP binding / membrane / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Peroxysomal long chain fatty acyl transporter / ABC transporter transmembrane region 2 / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / 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. ...Peroxysomal long chain fatty acyl transporter / ABC transporter transmembrane region 2 / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / 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
ABC transporter domain-containing protein / ATP-binding cassette sub-family D member 1
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.59 Å
AuthorsChen ZP / Xu D / Wang L / Mao YX / Yang L / Cheng MT / Hou WT / Chen YX / Zhou CZ
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071206 China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1.
Authors: Zhi-Peng Chen / Da Xu / Liang Wang / Yao-Xu Mao / Yang Li / Meng-Ting Cheng / Cong-Zhao Zhou / Wen-Tao Hou / Yuxing Chen /
Abstract: Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for β-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we ...Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for β-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we report three cryogenic electron microscopy structures of ABCD1: the apo-form, substrate- and ATP-bound forms. Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3'-phospho-ADP moiety of CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrates snapshots of ABCD1-mediated substrate transport cycle. It advances our understanding on the selective oxidation of fatty acids and molecular pathology of X-ALD.
History
DepositionNov 15, 2021-
Header (metadata) releaseMay 18, 2022-
Map releaseMay 18, 2022-
UpdateJun 26, 2024-
Current statusJun 26, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32224.png

Downloads & links

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Map

FileDownload / File: emd_32224.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.38
Minimum - Maximum-2.3759751 - 3.3453004
Average (Standard dev.)0.0063964683 (±0.08688968)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 235.40001 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : human peroxisomal ABCD1

EntireName: human peroxisomal ABCD1
Components
  • Organelle or cellular component: human peroxisomal ABCD1
    • Protein or peptide: Peroxisomal Membrane Protein related,ATP-binding cassette sub-family D member 1
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethyl] docosanethioate

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Supramolecule #1: human peroxisomal ABCD1

SupramoleculeName: human peroxisomal ABCD1 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Molecular weightTheoretical: 175.6 kDa/nm

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Macromolecule #1: Peroxisomal Membrane Protein related,ATP-binding cassette sub-fam...

MacromoleculeName: Peroxisomal Membrane Protein related,ATP-binding cassette sub-family D member 1
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
EC number: Hydrolases; Acting on ester bonds; Thioester hydrolases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.931 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTSVQSKFL ETGIDPEKRK KALLVGAAGV AAVAVAHWVS LRKSQKSHH KMEKEDSVAS DGTPKKNKKA GMNRVFLQRL LWLLRLLFPR VLCRETGLLA LHSAALVSRT FLSVYVARLD G RLARCIVR ...String:
MASWSHPQFE KGGGARGGSG GGSWSHPQFE KGFDYKDDDD KGTSVQSKFL ETGIDPEKRK KALLVGAAGV AAVAVAHWVS LRKSQKSHH KMEKEDSVAS DGTPKKNKKA GMNRVFLQRL LWLLRLLFPR VLCRETGLLA LHSAALVSRT FLSVYVARLD G RLARCIVR KDPRAFGWQL LQWLLIALPA TFVNSAIRYL EGQLALSFRS RLVAHAYRLY FSQQTYYRVS NMDGRLRNPD QS LTEDVVA FAASVAHLYS NLTKPLLDVA VTSYTLLRAA RSRGAGTAWP SAIAGLVVFL TANVLRAFSP KFGELVAEEA RRK GELRYM HSRVVANSEE IAFYGGHEVE LALLQRSYQD LASQINLILL ERLWYVMLEQ FLMKYVWSAS GLLMVAVPII TATG YSESD AEAVKKAALE KKEEELVSER TEAFTIARNL LTAAADAIER IMSSYKEVTE LAGYTARVHE MFQVFEDVQR CHFKR PREL EDAQAGSGTI GRSGVRVEGP LKIRGQVVDV EQGIICENIP IVTPSGEVVV ASLNIRVEEG MHLLITGPNG CGKSSL FRI LGGLWPTYGG VLYKPPPQRM FYIPQRPYMS VGSLRDQVIY PDSVEDMQRK GYSEQDLEAI LDVVHLHHIL QREGGWE AM CDWKDVLSGG EKQRIGMARM FYHRPKYALL DECTSAVSID VEGKIFQAAK DAGIALLSIT HRPSLWKYHT HLLQFDGE G GWKFEKLDSA ARLSLTEEKQ RLEQQLAGIP KMQRRLQELC QILGEAVAPA HVPAPSPQGP GGLQGAST

UniProtKB: ABC transporter domain-containing protein, ATP-binding cassette sub-family D member 1

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Macromolecule #2: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #3: S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidany...

MacromoleculeName: S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino] ...Name: S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethyl] docosanethioate
type: ligand / ID: 3 / Number of copies: 2 / Formula: FFI
Molecular weightTheoretical: 1.090102 KDa
Chemical component information

ChemComp-FFI:
S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethyl] docosanethioate

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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

Concentration8 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 8 K / Instrument: FEI VITROBOT MARK IV

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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 opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: -2.0 µm / Nominal defocus min: -1.5 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 336741
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 3

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-7vzb:
Cryo-EM structure of C22:0-CoA bound human very long-chain fatty acid ABC transporter ABCD1

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