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- PDB-9fl7: Cryo-EM structure of human AK2 bound to reduced human AIFM1 (resi... -

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Basic information

Entry
Database: PDB / ID: 9fl7
TitleCryo-EM structure of human AK2 bound to reduced human AIFM1 (residues 102-613), class 3
Components
  • Adenylate kinase 2, mitochondrial
  • Apoptosis-inducing factor 1, mitochondrial
KeywordsFLAVOPROTEIN / Mitochondria / Mitochondrial Intermembrane Space / IMS / Mitochondrial Inner Membrane / IM / Apoptosis-inducing Factor 1 / Adenylate Kinase
Function / homology
Function and homology information


AMP metabolic process / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / mitochondrial disulfide relay system / cellular response to aldosterone / ADP biosynthetic process / mitochondrial respiratory chain complex assembly / protein import into mitochondrial intermembrane space / NAD(P)H oxidase H2O2-forming activity / poly-ADP-D-ribose binding / adenylate kinase ...AMP metabolic process / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / mitochondrial disulfide relay system / cellular response to aldosterone / ADP biosynthetic process / mitochondrial respiratory chain complex assembly / protein import into mitochondrial intermembrane space / NAD(P)H oxidase H2O2-forming activity / poly-ADP-D-ribose binding / adenylate kinase / AMP kinase activity / nucleobase-containing small molecule interconversion / positive regulation of necroptotic process / Interconversion of nucleotide di- and triphosphates / oxidoreductase activity, acting on NAD(P)H / response to L-glutamate / sperm mitochondrial sheath / NADH dehydrogenase activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / ATP metabolic process / cellular response to nitric oxide / FAD binding / response to ischemia / cellular response to estradiol stimulus / mitochondrial intermembrane space / response to toxic substance / cellular response to hydrogen peroxide / neuron differentiation / positive regulation of neuron apoptotic process / cellular response to hypoxia / protein dimerization activity / mitochondrial inner membrane / positive regulation of apoptotic process / apoptotic process / perinuclear region of cytoplasm / mitochondrion / DNA binding / extracellular exosome / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Adenylate kinase 2 / Mitochondrial apoptosis-inducing factor, C-terminal domain / Apoptosis-inducing factor, mitochondrion-associated, C-term / Apoptosis-inducing factor, mitochondrion-associated, C-term / Adenylate kinase, active site lid domain / Adenylate kinase, active site lid / : / Adenylate kinase subfamily / Adenylate kinase, conserved site / Adenylate kinase signature. ...Adenylate kinase 2 / Mitochondrial apoptosis-inducing factor, C-terminal domain / Apoptosis-inducing factor, mitochondrion-associated, C-term / Apoptosis-inducing factor, mitochondrion-associated, C-term / Adenylate kinase, active site lid domain / Adenylate kinase, active site lid / : / Adenylate kinase subfamily / Adenylate kinase, conserved site / Adenylate kinase signature. / Adenylate kinase/UMP-CMP kinase / Adenylate kinase / FAD/NAD-linked reductase, dimerisation domain superfamily / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / FAD/NAD(P)-binding domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Apoptosis-inducing factor 1, mitochondrial / Adenylate kinase 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLauer, S.M. / Spahn, C.M.T. / Schwefel, D.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)SCHW 1851/1-1 Germany
CitationJournal: Mol Cell / Year: 2025
Title: An NADH-controlled gatekeeper of ATP synthase.
Authors: Fabian Schildhauer / Petra S J Ryl / Simon M Lauer / Swantje Lenz / Ayşe Berçin Barlas / Vasileios R Ouzounidis / Kate Jeffrey / Daniel-Cosmin Marcu / Francis J O'Reilly / Andrea Graziadei ...Authors: Fabian Schildhauer / Petra S J Ryl / Simon M Lauer / Swantje Lenz / Ayşe Berçin Barlas / Vasileios R Ouzounidis / Kate Jeffrey / Daniel-Cosmin Marcu / Francis J O'Reilly / Andrea Graziadei / Marchel Stuiver / Kita Schmidt / Helge Ewers / Christian M T Spahn / Ezgi Karaca / Karl Emanuel Busch / Dhanya Cheerambathur / David Schwefel / Juri Rappsilber /
Abstract: ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic ...ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH dependent and influenced by glycolysis, linking it to the cell's metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases.
History
DepositionJun 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 14, 2025Provider: repository / Type: Initial release
Revision 1.0May 14, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 14, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 14, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 14, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 14, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0May 14, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Apoptosis-inducing factor 1, mitochondrial
B: Apoptosis-inducing factor 1, mitochondrial
D: Adenylate kinase 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,0787
Polymers140,1803
Non-polymers2,8984
Water00
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 Apoptosis-inducing factor 1, mitochondrial / Programmed cell death protein 8


Mass: 56516.148 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Residues 1-101 deleted / Source: (gene. exp.) Homo sapiens (human) / Gene: AIFM1, AIF, PDCD8 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O95831, Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors
#2: Protein Adenylate kinase 2, mitochondrial / AK 2 / ATP-AMP transphosphorylase 2 / ATP:AMP phosphotransferase / Adenylate monophosphate kinase


Mass: 27147.502 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AK2, ADK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P54819, adenylate kinase
#3: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
#4: 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 modificationY

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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 1 with Adenylate kinase 2
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.14 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3)
Buffer solutionpH: 7.8
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMTris-HClTris-HCl1
2150 mMSodium chlorideNaCl1
34 mMMagnesium chlorideMgCl21
40.5 mMTris(2-carboxyethyl)phosphineTCEP1
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 99 % / Chamber temperature: 277.15 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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.20.1_4487:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1748043
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 147096 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029162
ELECTRON MICROSCOPYf_angle_d0.48512418
ELECTRON MICROSCOPYf_dihedral_angle_d7.2031245
ELECTRON MICROSCOPYf_chiral_restr0.0431374
ELECTRON MICROSCOPYf_plane_restr0.0041582

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