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- EMDB-50532: Cryo-EM structure of human AK2 bound to reduced human AIFM1 (resi... -

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Basic information

Entry
Database: EMDB / ID: EMD-50532
TitleCryo-EM structure of human AK2 bound to reduced human AIFM1 (residues 102-613), class 3
Map dataMain map (sharpened)
Sample
  • Complex: Complex of Apoptosis-inducing factor 1 with Adenylate kinase 2
    • Protein or peptide: Apoptosis-inducing factor 1, mitochondrial
    • Protein or peptide: Adenylate kinase 2, mitochondrial
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
KeywordsMitochondria / Mitochondrial Intermembrane Space / IMS / Mitochondrial Inner Membrane / IM / Apoptosis-inducing Factor 1 / Adenylate Kinase / FLAVOPROTEIN
Function / homology
Function and homology information


AMP metabolic process / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / protein import into the intermembrane space via the disulfide relay system / ADP biosynthetic process / cellular response to aldosterone / mitochondrial respiratory chain complex assembly / protein import into mitochondrial intermembrane space / poly-ADP-D-ribose binding / NAD(P)H oxidase H2O2-forming activity / adenylate kinase ...AMP metabolic process / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / protein import into the intermembrane space via the disulfide relay system / ADP biosynthetic process / cellular response to aldosterone / mitochondrial respiratory chain complex assembly / protein import into mitochondrial intermembrane space / poly-ADP-D-ribose binding / NAD(P)H oxidase H2O2-forming activity / adenylate kinase / AMP kinase activity / nucleobase-containing small molecule interconversion / positive regulation of necroptotic process / Interconversion of nucleotide di- and triphosphates / response to L-glutamate / sperm mitochondrial sheath / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / NADH dehydrogenase activity / oxidoreductase activity, acting on NAD(P)H / sperm head-tail coupling apparatus / 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 / cytoplasm / cytosol
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
Apoptosis-inducing factor 1, mitochondrial / Adenylate kinase 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLauer SM / Spahn CMT / Schwefel D
Funding support Germany, 1 items
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, 2024-
Header (metadata) releaseMay 14, 2025-
Map releaseMay 14, 2025-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50532.png

Downloads & links

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Map

FileDownload / File: emd_50532.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map (sharpened)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.7 Å/pix.
x 160 pix.
= 272. Å		1.7 Å/pix.
x 160 pix.
= 272. Å		1.7 Å/pix.
x 160 pix.
= 272. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.7 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-2.4641132 - 5.5620847
Average (Standard dev.)-0.0014503052 (±0.15252043)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50532_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_50532_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_50532_half_map_2.map
AnnotationHalf map B
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Apoptosis-inducing factor 1 with Adenylate kinase 2

EntireName: Complex of Apoptosis-inducing factor 1 with Adenylate kinase 2
Components
  • Complex: Complex of Apoptosis-inducing factor 1 with Adenylate kinase 2
    • Protein or peptide: Apoptosis-inducing factor 1, mitochondrial
    • Protein or peptide: Adenylate kinase 2, mitochondrial
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE

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Supramolecule #1: Complex of Apoptosis-inducing factor 1 with Adenylate kinase 2

SupramoleculeName: Complex of Apoptosis-inducing factor 1 with Adenylate kinase 2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140 KDa

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Macromolecule #1: Apoptosis-inducing factor 1, mitochondrial

MacromoleculeName: Apoptosis-inducing factor 1, mitochondrial / type: protein_or_peptide / ID: 1 / Details: Residues 1-101 deleted / Number of copies: 2 / Enantiomer: LEVO
EC number: Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.516148 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: GIDPFTLGLT PEQKQKKAAL SASEGEEVPQ DKAPSHVPFL LIGGGTAAFA AARSIRARDP GARVLIVSED PELPYMRPPL SKELWFSDD PNVTKTLRFK QWNGKERSIY FQPPSFYVSA QDLPHIENGG VAVLTGKKVV QLDVRDNMVK LNDGSQITYE K CLIATGGT ...String:
GIDPFTLGLT PEQKQKKAAL SASEGEEVPQ DKAPSHVPFL LIGGGTAAFA AARSIRARDP GARVLIVSED PELPYMRPPL SKELWFSDD PNVTKTLRFK QWNGKERSIY FQPPSFYVSA QDLPHIENGG VAVLTGKKVV QLDVRDNMVK LNDGSQITYE K CLIATGGT PRSLSAIDRA GAEVKSRTTL FRKIGDFRSL EKISREVKSI TIIGGGFLGS ELACALGRKA RALGTEVIQL FP EKGNMGK ILPEYLSNWT MEKVRREGVK VMPNAIVQSV GVSSGKLLIK LKDGRKVETD HIVAAVGLEP NVELAKTGGL EID SDFGGF RVNAELQARS NIWVAGDAAC FYDIKLGRRR VEHHDHAVVS GRLAGENMTG AAKPYWHQSM FWSDLGPDVG YEAI GLVDS SLPTVGVFAK ATAQDNPKSA TEQSGTGIRS ESETESEASE ITIPPSTPAV PQAPVQGEDY GKGVIFYLRD KVVVG IVLW NIFNRMPIAR KIIKDGEQHE DLNEVAKLFN IHED

UniProtKB: Apoptosis-inducing factor 1, mitochondrial

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Macromolecule #2: Adenylate kinase 2, mitochondrial

MacromoleculeName: Adenylate kinase 2, mitochondrial / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: adenylate kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.147502 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: GIDPFTMAPS VPAAEPEYPK GIRAVLLGPP GAGKGTQAPR LAENFCVCHL ATGDMLRAMV ASGSELGKKL KATMDAGKLV SDEMVVELI EKNLETPLCK NGFLLDGFPR TVRQAEMLDD LMEKRKEKLD SVIEFSIPDS LLIRRITGRL IHPKSGRSYH E EFNPPKEP ...String:
GIDPFTMAPS VPAAEPEYPK GIRAVLLGPP GAGKGTQAPR LAENFCVCHL ATGDMLRAMV ASGSELGKKL KATMDAGKLV SDEMVVELI EKNLETPLCK NGFLLDGFPR TVRQAEMLDD LMEKRKEKLD SVIEFSIPDS LLIRRITGRL IHPKSGRSYH E EFNPPKEP MKDDITGEPL IRRSDDNEKA LKIRLQAYHT QTTPLIEYYR KRGIHSAIDA SQTPDVVFAS ILAAFSKATC KD LVMFI

UniProtKB: Adenylate kinase 2, mitochondrial

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Macromolecule #3: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

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Macromolecule #4: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 4 / Number of copies: 2 / Formula: FAD
Molecular weightTheoretical: 785.55 Da
Chemical component information

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

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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

Concentration0.1 mg/mL
BufferpH: 7.8
Component:
ConcentrationFormulaName
10.0 mMTris-HClTris-HCl
150.0 mMNaClSodium chloride
4.0 mMMgCl2Magnesium chloride
0.5 mMTCEPTris(2-carboxyethyl)phosphine
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 99 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1748043
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab initio
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 147096
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 6 / Software - Name: cryoSPARC

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-9fl7:
Cryo-EM structure of human AK2 bound to reduced human AIFM1 (residues 102-613), class 3

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