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- PDB-8phf: Cryo-EM structure of human ACAD9-S191A -

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Basic information

Entry
Database: PDB / ID: 8phf
TitleCryo-EM structure of human ACAD9-S191A
ComponentsComplex I assembly factor ACAD9, mitochondrial
KeywordsFLAVOPROTEIN / Oxidative phosphorylation (OXPHOS) / Fatty Acid Oxidation (FAO) / Mitochondrial Complex I Assembly Complex (MCIA) / Amyloid-beta / SIGNALING PROTEIN
Function / homology
Function and homology information


Oxidoreductases; Acting on the CH-CH group of donors; With a flavin as acceptor / long-chain fatty acyl-CoA dehydrogenase activity / medium-chain fatty acyl-CoA dehydrogenase activity / medium-chain fatty acid metabolic process / long-chain fatty acid metabolic process / Complex I biogenesis / acyl-CoA dehydrogenase activity / mitochondrial respiratory chain complex I assembly / mitochondrial membrane / flavin adenine dinucleotide binding ...Oxidoreductases; Acting on the CH-CH group of donors; With a flavin as acceptor / long-chain fatty acyl-CoA dehydrogenase activity / medium-chain fatty acyl-CoA dehydrogenase activity / medium-chain fatty acid metabolic process / long-chain fatty acid metabolic process / Complex I biogenesis / acyl-CoA dehydrogenase activity / mitochondrial respiratory chain complex I assembly / mitochondrial membrane / flavin adenine dinucleotide binding / mitochondrial inner membrane / dendrite / mitochondrion / nucleus
Similarity search - Function
: / ACAD9/ACADV, C-terminal domain / Acyl-CoA dehydrogenases signature 1. / Acyl-CoA dehydrogenases signature 2. / Acyl-CoA dehydrogenase, conserved site / Acyl-CoA dehydrogenase/oxidase C-terminal / Acyl-CoA dehydrogenase/oxidase, N-terminal / Acyl-CoA dehydrogenase, N-terminal domain / Acyl-CoA dehydrogenase, C-terminal domain / Acyl-CoA oxidase/dehydrogenase, middle domain ...: / ACAD9/ACADV, C-terminal domain / Acyl-CoA dehydrogenases signature 1. / Acyl-CoA dehydrogenases signature 2. / Acyl-CoA dehydrogenase, conserved site / Acyl-CoA dehydrogenase/oxidase C-terminal / Acyl-CoA dehydrogenase/oxidase, N-terminal / Acyl-CoA dehydrogenase, N-terminal domain / Acyl-CoA dehydrogenase, C-terminal domain / Acyl-CoA oxidase/dehydrogenase, middle domain / Acyl-CoA dehydrogenase, middle domain / Acyl-CoA dehydrogenase/oxidase, N-terminal domain superfamily / Acyl-CoA oxidase/dehydrogenase, middle domain superfamily / Acyl-CoA dehydrogenase/oxidase, N-terminal and middle domain superfamily / Acyl-CoA dehydrogenase-like, C-terminal
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / Complex I assembly factor ACAD9, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsMcGregor, L. / Acajjaoui, S. / Desfosses, A. / Saidi, M. / Bacia-Verloop, M. / Schwarz, J.J. / Juyoux, P. / Von Velsen, J. / Bowler, M.W. / McCarthy, A. ...McGregor, L. / Acajjaoui, S. / Desfosses, A. / Saidi, M. / Bacia-Verloop, M. / Schwarz, J.J. / Juyoux, P. / Von Velsen, J. / Bowler, M.W. / McCarthy, A. / Kandiah, E. / Gutsche, I. / Soler-Lopez, M.
Funding support France, 1items
OrganizationGrant numberCountry
Other government France
CitationJournal: Nat Commun / Year: 2023
Title: The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
Authors: Lindsay McGregor / Samira Acajjaoui / Ambroise Desfosses / Melissa Saïdi / Maria Bacia-Verloop / Jennifer J Schwarz / Pauline Juyoux / Jill von Velsen / Matthew W Bowler / Andrew A McCarthy ...Authors: Lindsay McGregor / Samira Acajjaoui / Ambroise Desfosses / Melissa Saïdi / Maria Bacia-Verloop / Jennifer J Schwarz / Pauline Juyoux / Jill von Velsen / Matthew W Bowler / Andrew A McCarthy / Eaazhisai Kandiah / Irina Gutsche / Montserrat Soler-Lopez /
Abstract: The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's ...The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.
History
DepositionJun 19, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Complex I assembly factor ACAD9, mitochondrial
B: Complex I assembly factor ACAD9, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,2564
Polymers131,6852
Non-polymers1,5712
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14340 Å2
ΔGint-85 kcal/mol
Surface area41720 Å2

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Components

#1: Protein Complex I assembly factor ACAD9, mitochondrial / Acyl-CoA dehydrogenase family member 9 / ACAD-9


Mass: 65842.523 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACAD9 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9H845, Oxidoreductases; Acting on the CH-CH group of donors; With a flavin as acceptor
#2: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
Has ligand of interestY
Has protein modificationN

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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: ACAD9 S191A / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.120 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DARK FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 163409 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038803
ELECTRON MICROSCOPYf_angle_d0.57511884
ELECTRON MICROSCOPYf_dihedral_angle_d5.681183
ELECTRON MICROSCOPYf_chiral_restr0.0411346
ELECTRON MICROSCOPYf_plane_restr0.0041509

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