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- EMDB-51515: Interaction with AK2A links AIFM1 to cellular energy metabolism. ... -

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Entry
Database: EMDB / ID: EMD-51515
TitleInteraction with AK2A links AIFM1 to cellular energy metabolism. The cryo-EM structure of dimeric AIFM1 engaged to MIA40.
Map data
Sample
  • Complex: Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with the Mitochondrial intermembrane space import and assembly protein 40 (MIA40)
    • Protein or peptide: Mitochondrial intermembrane space import and assembly protein 40
    • Protein or peptide: Apoptosis-inducing factor 1, mitochondrial
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: water
KeywordsComplex / Homodimer / NADH / FAD / Reduced / FLAVOPROTEIN
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
Apoptosis-inducing factor 1, mitochondrial / Mitochondrial intermembrane space import and assembly protein 40
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.36 Å
AuthorsRothemann RA / Pavlenko EA / Gerlich S / Grobushkin P / Mostert S / Stobbe D / Racho J / Stillger K / Lapacz K / Petrungaro C ...Rothemann RA / Pavlenko EA / 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 THD / Poepsel SP / Riemer J
Funding support Germany, 4 items
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, 2024-
Header (metadata) releaseJul 9, 2025-
Map releaseJul 9, 2025-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51515.png

Downloads & links

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Map

FileDownload / File: emd_51515.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 288 pix.
= 188.352 Å		0.65 Å/pix.
x 288 pix.
= 188.352 Å		0.65 Å/pix.
x 288 pix.
= 188.352 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.654 Å
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Contour LevelBy AUTHOR: 0.0827
Minimum - Maximum-0.13690378 - 0.2928554
Average (Standard dev.)-0.00021755611 (±0.009513352)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 188.35199 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51515_msk_1.map
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Mask #2

Fileemd_51515_msk_2.map
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Additional map: Sharpened Map

Fileemd_51515_additional_1.map
AnnotationSharpened_Map
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Half map: #2

Fileemd_51515_half_map_1.map
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Half map: #1

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Sample components

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Entire : Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with...

EntireName: Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with the Mitochondrial intermembrane space import and assembly protein 40 (MIA40)
Components
  • Complex: Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with the Mitochondrial intermembrane space import and assembly protein 40 (MIA40)
    • Protein or peptide: Mitochondrial intermembrane space import and assembly protein 40
    • Protein or peptide: Apoptosis-inducing factor 1, mitochondrial
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: water

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Supramolecule #1: Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with...

SupramoleculeName: Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) with the Mitochondrial intermembrane space import and assembly protein 40 (MIA40)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Mitochondrial intermembrane space import and assembly protein 40

MacromoleculeName: Mitochondrial intermembrane space import and assembly protein 40
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.050369 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MSYCRQEGKD RIIFVTKEDH ETPSSAELVA DDPNDPYEEH GLILPNGNIN WNSPSLGGMA SGPCGEQFKS AFSCFHYSTE EIKGSDCVD QFRAMQECMQ KYPDLYPQED EDEEEEREKK PAEQAEETAP IEATATKEEE GSSLEHHHHH H

UniProtKB: Mitochondrial intermembrane space import and assembly protein 40

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Macromolecule #2: Apoptosis-inducing factor 1, mitochondrial

MacromoleculeName: Apoptosis-inducing factor 1, mitochondrial / type: protein_or_peptide / ID: 2 / 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: 58.902832 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MASMTGGQQM GRGSEFMGGL TPEQKQKKAA LSASEGEEVP QDKAPSHVPF LLIGGGTAAF AAARSIRARD PGARVLIVSE DPELPYMRP PLSKELWFSD DPNVTKTLRF KQWNGKERSI YFQPPSFYVS AQDLPHIENG GVAVLTGKKV VQLDVRDNMV K LNDGSQIT ...String:
MASMTGGQQM GRGSEFMGGL TPEQKQKKAA LSASEGEEVP QDKAPSHVPF LLIGGGTAAF AAARSIRARD PGARVLIVSE DPELPYMRP PLSKELWFSD DPNVTKTLRF KQWNGKERSI YFQPPSFYVS AQDLPHIENG GVAVLTGKKV VQLDVRDNMV K LNDGSQIT YEKCLIATGG TPRSLSAIDR AGAEVKSRTT LFRKIGDFRS LEKISREVKS ITIIGGGFLG SELACALGRK AR ALGTEVI QLFPEKGNMG KILPEYLSNW TMEKVRREGV KVMPNAIVQS VGVSSGKLLI KLKDGRKVET DHIVAAVGLE PNV ELAKTG GLEIDSDFGG FRVNAELQAR SNIWVAGDAA CFYDIKLGRR RVEHHDHAVV SGRLAGENMT GAAKPYWHQS MFWS DLGPD VGYEAIGLVD SSLPTVGVFA KATAQDNPKS ATEQSGTGIR SESETESEAS EITIPPSTPA VPQAPVQGED YGKGV IFYL RDKVVVGIVL WNIFNRMPIA RKIIKDGEQH EDLNEVAKLF NIHEDAAALE HHHHHH

UniProtKB: Apoptosis-inducing factor 1, mitochondrial

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Macromolecule #3: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 3 / 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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Macromolecule #4: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 4 / 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 #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 17 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

BufferpH: 7.4
Component:
ConcentrationFormulaName
0.1 mMNADHNicotinamide adenine dinucleotide
100.0 mMNaClSodium Chloride
20.0 mMTris/ClTris(hydroxymethyl)aminomethan
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: OTHER / Nominal defocus max: 1.7 µm / Nominal defocus min: 0.7000000000000001 µm
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

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: ALPHAFOLD prediction
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.36 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 291656
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9gqz:
Interaction with AK2A links AIFM1 to cellular energy metabolism. The cryo-EM structure of dimeric AIFM1 engaged to MIA40.

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