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- PDB-9gqz: Interaction with AK2A links AIFM1 to cellular energy metabolism. ... -

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Basic information

Entry
Database: PDB / ID: 9gqz
TitleInteraction with AK2A links AIFM1 to cellular energy metabolism. The cryo-EM structure of dimeric AIFM1 engaged to MIA40.
Components
  • Apoptosis-inducing factor 1, mitochondrial
  • Mitochondrial intermembrane space import and assembly protein 40
KeywordsFLAVOPROTEIN / Complex / Homodimer / NADH / FAD / Reduced
Function / homology
Function and homology information


: / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / mitochondrial disulfide relay system / mitochondrial respiratory chain complex assembly / positive regulation of cellular respiration / protein import into mitochondrial intermembrane space / NAD(P)H oxidase H2O2-forming activity / poly-ADP-D-ribose binding / cellular response to aldosterone / Mitochondrial protein import ...: / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / mitochondrial disulfide relay system / mitochondrial respiratory chain complex assembly / positive regulation of cellular respiration / protein import into mitochondrial intermembrane space / NAD(P)H oxidase H2O2-forming activity / poly-ADP-D-ribose binding / cellular response to aldosterone / Mitochondrial protein import / positive regulation of necroptotic process / regulation of protein export from nucleus / oxidoreductase activity, acting on NAD(P)H / mitochondrial DNA repair / response to L-glutamate / protein-disulfide reductase activity / NADH dehydrogenase activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to nitric oxide / FAD binding / cellular response to leukemia inhibitory factor / response to ischemia / cellular response to estradiol stimulus / mitochondrial intermembrane space / cellular response to hydrogen peroxide / response to toxic substance / neuron differentiation / positive regulation of neuron apoptotic process / cellular response to oxidative stress / cellular response to hypoxia / mitochondrial inner membrane / protein dimerization activity / positive regulation of apoptotic process / apoptotic process / perinuclear region of cytoplasm / mitochondrion / DNA binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitochondrial intermembrane space import and assembly protein 40 / Mitochondrial apoptosis-inducing factor, C-terminal domain / Apoptosis-inducing factor, mitochondrion-associated, C-term / Apoptosis-inducing factor, mitochondrion-associated, C-term / : / FAD/NAD-linked reductase, dimerisation domain superfamily / CHCH / CHCH domain / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase ...Mitochondrial intermembrane space import and assembly protein 40 / Mitochondrial apoptosis-inducing factor, C-terminal domain / Apoptosis-inducing factor, mitochondrion-associated, C-term / Apoptosis-inducing factor, mitochondrion-associated, C-term / : / FAD/NAD-linked reductase, dimerisation domain superfamily / CHCH / CHCH domain / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / Coiled coil-helix-coiled coil-helix (CHCH) domain profile. / FAD/NAD(P)-binding domain superfamily
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Apoptosis-inducing factor 1, mitochondrial / Mitochondrial intermembrane space import and assembly protein 40
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.36 Å
AuthorsRothemann, R.A. / Pavlenko, E.A. / Gerlich, S. / Grobushkin, P. / Mostert, S. / Stobbe, D. / Racho, J. / Stillger, K. / Lapacz, K. / Petrungaro, C. ...Rothemann, R.A. / Pavlenko, E.A. / Gerlich, S. / Grobushkin, P. / Mostert, S. / Stobbe, D. / Racho, J. / Stillger, K. / Lapacz, K. / Petrungaro, C. / Dengjel, J. / Neundorf, I. / Bano, D. / Mondal, M. / Weiss, K. / Ehninger, D. / Nguyen, T.H.D. / Poepsel, S.P. / Riemer, J.
Funding support Germany, 4items
OrganizationGrant numberCountry
German Research Foundation (DFG)RI2150/5-1 Germany
German Research Foundation (DFG)SPP2453 Germany
German Research Foundation (DFG)RTG2550/1 Germany
German Research Foundation (DFG)455 SFB1430 Germany
CitationJournal: Mol Cell / Year: 2025
Title: Interaction with AK2A links AIFM1 to cellular energy metabolism.
Authors: Robin Alexander Rothemann / Egor Pavlenko / Mrityunjoy Mondal / Sarah Gerlich / Pavel Grobushkin / Sebastian Mostert / Julia Racho / Konstantin Weiss / Dylan Stobbe / Katharina Stillger / ...Authors: Robin Alexander Rothemann / Egor Pavlenko / Mrityunjoy Mondal / Sarah Gerlich / Pavel Grobushkin / Sebastian Mostert / Julia Racho / Konstantin Weiss / Dylan Stobbe / Katharina Stillger / Kim Lapacz / Silja Lucia Salscheider / Carmelina Petrungaro / Dan Ehninger / Thi Hoang Duong Nguyen / Jörn Dengjel / Ines Neundorf / Daniele Bano / Simon Poepsel / Jan Riemer /
Abstract: Apoptosis-inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40/CHCHD4, the central component of the mitochondrial disulfide ...Apoptosis-inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40/CHCHD4, the central component of the mitochondrial disulfide relay, accounts for some, but not all, aspects of AIFM1 function. We provide a high-confidence AIFM1 interactome that elucidates functional partners within the mitochondrial intermembrane space. We found that AIFM1 binding to adenylate kinase 2 (AK2), an essential enzyme that maintains cellular adenine nucleotide pools, depends on the AK2 C-terminal domain. High-resolution cryoelectron microscopy (cryo-EM) and biochemical analyses showed that both MIA40 and AK2A bind the AIFM1 C-terminal β-sheet domain. Their binding enhances NADH oxidoreductase activity by locking an active dimer conformation and, in the case of MIA40, affecting the cofactor-binding site. The AIFM1-AK2A interaction is important during mitochondrial respiration because AIFM1 serves as a recruiting hub within the IMS, regulating mitochondrial bioenergetic output by creating hotspots of metabolic enzymes.
History
DepositionSep 10, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitochondrial intermembrane space import and assembly protein 40
F: Mitochondrial intermembrane space import and assembly protein 40
B: Apoptosis-inducing factor 1, mitochondrial
C: Apoptosis-inducing factor 1, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,8048
Polymers151,9064
Non-polymers2,8984
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Mitochondrial intermembrane space import and assembly protein 40 / Coiled-coil-helix-coiled-coil-helix domain-containing protein 4


Mass: 17050.369 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHCHD4, MIA40 / Production host: Escherichia coli (E. coli) / Strain (production host): ROSETTA 2 / References: UniProt: Q8N4Q1
#2: Protein Apoptosis-inducing factor 1, mitochondrial / Programmed cell death protein 8


Mass: 58902.832 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AIFM1, AIF, PDCD8 / Production host: Escherichia coli (E. coli) / Strain (production host): ROSETTA 2
References: UniProt: O95831, Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors
#3: 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
#4: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
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: Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with the Mitochondrial intermembrane space import and assembly protein 40 (MIA40)
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.2 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: ROSETTA 2 / Plasmid: pET-24a(+)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
10.1 mMNicotinamide adenine dinucleotideNADH1
2100 mMSodium ChlorideNaCl1
320 mMTris(hydroxymethyl)aminomethanTris/Cl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: SPOT SCAN
Electron lensMode: OTHER / Nominal defocus max: 1700 nm / Nominal defocus min: 700 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2cryoSPARCimage acquisition
3cryoSPARCmasking
4cryoSPARCCTF correction
5Cootmodel fitting
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.21_5207:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 291656 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027475
ELECTRON MICROSCOPYf_angle_d0.48910126
ELECTRON MICROSCOPYf_dihedral_angle_d6.2961194
ELECTRON MICROSCOPYf_chiral_restr0.0441109
ELECTRON MICROSCOPYf_plane_restr0.0041277

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