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- PDB-7rra: Cryo-EM Structure of Nanodisc reconstituted ABCD1 in inward open ... -

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Entry
Database: PDB / ID: 7rra
TitleCryo-EM Structure of Nanodisc reconstituted ABCD1 in inward open conformation
ComponentsATP-binding cassette sub-family D member 1
KeywordsTRANSPORT PROTEIN / VLCFA ABC transporter ABCD1
Function / homology
Function and homology information


ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / long-chain fatty acid catabolic process / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / alpha-linolenic acid metabolic process ...ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / long-chain fatty acid catabolic process / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / alpha-linolenic acid metabolic 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 / fatty acyl-CoA hydrolase activity / myelin maintenance / regulation of cellular response to oxidative stress / Hydrolases; Acting on ester bonds; Thioester hydrolases / positive regulation of fatty acid beta-oxidation / regulation of oxidative phosphorylation / linoleic acid metabolic process / 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 / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / ADP binding / mitochondrial membrane / peroxisome / protein heterodimerization activity / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / ATP hydrolysis activity / protein homodimerization activity / ATP binding / membrane / identical protein binding / cytosol / cytoplasm
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
ATP-binding cassette sub-family D member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsAlam, A. / Le, L.T.M. / Thompson, J.R.
Funding support United States, 2items
OrganizationGrant numberCountry
Other private
Other private United States
CitationJournal: Commun Biol / Year: 2022
Title: Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment.
Authors: Le Thi My Le / James Robert Thompson / Phuoc Xuan Dang / Janarjan Bhandari / Amer Alam /
Abstract: The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, ...The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairments including X-linked adrenoleukodystrophy (X-ALD). We present cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP dependent conformational spectrum. We identify features distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Our data suggest a transport mechanism where the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations and may aid ABCD1 targeted structure-based drug design.
History
DepositionAug 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
B: ATP-binding cassette sub-family D member 1
A: ATP-binding cassette sub-family D member 1


Theoretical massNumber of molelcules
Total (without water)166,0822
Polymers166,0822
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9960 Å2
ΔGint-76 kcal/mol
Surface area64360 Å2

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Components

#1: Protein ATP-binding cassette sub-family D member 1 / Adrenoleukodystrophy protein / ALDP


Mass: 83040.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCD1, ALD / Production host: Homo sapiens (human) / References: UniProt: P33897, EC: 7.6.2.4

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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: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs in Conformation open to cytoplasm (Inward open)
Type: COMPLEX
Details: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular ...Details: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular weight of 0.0829 MDa is for the monomer. The assembly is a homodimer. The dimer was confirmed using SEC.
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.0829 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Details: 25mM HEPES pH 7.5, 150mM NaCl, 5mM ATP gammaS, 10mM Magnesium Chloride
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K

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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 recordingAverage exposure time: 60 sec. / Electron dose: 60 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20rc3_4406: / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4GctfCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
12RELION3.1classification
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 139009 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL
Atomic model buildingPDB-ID: 6JBJ

6jbj

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039820
ELECTRON MICROSCOPYf_angle_d0.60813298
ELECTRON MICROSCOPYf_dihedral_angle_d13.7623628
ELECTRON MICROSCOPYf_chiral_restr0.041484
ELECTRON MICROSCOPYf_plane_restr0.0031690

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