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- EMDB-51516: Interaction with AK2A links AIFM1 to cellular energy metabolism. ... -

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Entry
Database: EMDB / ID: EMD-51516
TitleInteraction with AK2A links AIFM1 to cellular energy metabolism. The cryo-EM structure of dimeric AIFM1 bound by AK2A.
Map data
Sample
  • Complex: Dimeric Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) bound by adenylate kinase 2 isoform A (AK2A)
    • Protein or peptide: Adenylate kinase 2, mitochondrial
    • Protein or peptide: Apoptosis-inducing factor 1, mitochondrial
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: water
KeywordsComplex / Tetramer / NADH / FAD / Reduced / FLAVOPROTEIN
Function / homology
Function and homology information


AMP metabolic process / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / mitochondrial disulfide relay system / 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 ...AMP metabolic process / Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / mitochondrial disulfide relay system / 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 / cellular response to aldosterone / positive regulation of necroptotic process / Interconversion of nucleotide di- and triphosphates / oxidoreductase activity, acting on NAD(P)H / sperm mitochondrial sheath / response to L-glutamate / 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 / cellular response to hydrogen peroxide / response to toxic substance / neuron differentiation / positive regulation of neuron apoptotic process / cellular response to hypoxia / mitochondrial inner membrane / protein dimerization activity / 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
Apoptosis-inducing factor 1, mitochondrial / Adenylate kinase 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 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_51516.png

Downloads & links

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Map

FileDownload / File: emd_51516.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.58 Å/pix.
x 416 pix.
= 241.28 Å		0.58 Å/pix.
x 416 pix.
= 241.28 Å		0.58 Å/pix.
x 416 pix.
= 241.28 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.58 Å
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Contour LevelBy AUTHOR: 0.0314
Minimum - Maximum-0.050561033 - 0.11182194
Average (Standard dev.)-0.00003180303 (±0.002384701)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 241.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51516_msk_1.map
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Mask #2

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Additional map: #1

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Half map: #2

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Sample components

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Entire : Dimeric Complex of Apoptosis inducing factor mitochondrial 1 (AIF...

EntireName: Dimeric Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) bound by adenylate kinase 2 isoform A (AK2A)
Components
  • Complex: Dimeric Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) bound by adenylate kinase 2 isoform A (AK2A)
    • Protein or peptide: Adenylate kinase 2, mitochondrial
    • Protein or peptide: Apoptosis-inducing factor 1, mitochondrial
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: water

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Supramolecule #1: Dimeric Complex of Apoptosis inducing factor mitochondrial 1 (AIF...

SupramoleculeName: Dimeric Complex of Apoptosis inducing factor mitochondrial 1 (AIFM1) bound by adenylate kinase 2 isoform A (AK2A)
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: Adenylate kinase 2, mitochondrial

MacromoleculeName: Adenylate kinase 2, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: adenylate kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.516811 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAPSVPAAEP EYPKGIRAVL LGPPGAGKGT QAPRLAENFC VCHLATGDML RAMVASGSEL GKKLKATMDA GKLVSDEMVV ELIEKNLET PLCKNGFLLD GFPRTVRQAE MLDDLMEKRK EKLDSVIEFS IPDSLLIRRI TGRLIHPKSG RSYHEEFNPP K EPMKDDIT ...String:
MAPSVPAAEP EYPKGIRAVL LGPPGAGKGT QAPRLAENFC VCHLATGDML RAMVASGSEL GKKLKATMDA GKLVSDEMVV ELIEKNLET PLCKNGFLLD GFPRTVRQAE MLDDLMEKRK EKLDSVIEFS IPDSLLIRRI TGRLIHPKSG RSYHEEFNPP K EPMKDDIT GEPLIRRSDD NEKALKIRLQ AYHTQTTPLI EYYRKRGIHS AIDASQTPDV VFASILAAFS KATCKDLVMF I

UniProtKB: Adenylate kinase 2, mitochondrial

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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: 23 / 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
Specialist opticsEnergy filter - Name: TFS Selectris
Image recordingFilm or detector model: FEI FALCON IV (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: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 307496
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-9gr0:
Interaction with AK2A links AIFM1 to cellular energy metabolism. The cryo-EM structure of dimeric AIFM1 bound by AK2A.

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