Q9Z0X1 (AIFM1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Apoptosis-inducing factor 1, mitochondrial
EC=1.-.-.-

Alternative name(s):
Programmed cell death protein 8

Gene names

Name:	Aifm1
Synonyms:	Aif, Pdcd8

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	612 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Probable oxidoreductase that has a dual role in controlling cellular life and death; during apoptosis, it is translocated from the mitochondria to the nucleus to function as a proapoptotic factor in a caspase-independent pathway, while in normal mitochondria, it functions as an antiapoptotic factor via its oxidoreductase activity. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Interacts with EIF3G,and thereby inhibits the EIF3 machinery and protein synthesis,and activates casapse-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Binds to DNA in a sequence-independent manner By similarity. Ref.1
Cofactor	FAD. Ref.1
Subunit structure	Interacts with XIAP/BIRC4. Interacts (via N-terminus) with EIF3G (via C-terminus) By similarity.
Subcellular location	Mitochondrion intermembrane space. Mitochondrion inner membrane By similarity. Cytoplasm By similarity. Cytoplasm › perinuclear region By similarity. Nucleus. Note: Proteolytic cleavage during or just after translocation into the mitochondrial intermembrane space (IMS) results in the formation of an inner-membrane-anchored mature form (AIFmit). During apoptosis, further proteolytic processing leads to a mature form, which is confined to the mitochondrial IMS in a soluble form (AIFsol). AIFsol is released to the cytoplasm in response to specific death signals, and translocated to the nucleus, where it induces nuclear apoptosis. Colocalizes with EIF3G in the nucleus and perinuclear region By similarity. Ref.1
Post-translational modification	Under normal conditions, a 54-residue N-terminal segment is first proteolytically removed during or just after translocation into the mitochondrial intermembrane space (IMS) by the mitochondrial processing peptidase (MPP) to form the inner-membrane-anchored mature form (AIFmit). During apoptosis, it is further proteolytically processed at amino-acid position 101 leading to the generation of the mature form, which is confined to the mitochondrial IMS in a soluble form (AIFsol). AIFsol is released to the cytoplasm in response to specific death signals, and translocated to the nucleus, where it induces nuclear apoptosis in a caspase-independent manner By similarity. Ubiquitination by XIAP/BIRC4 does not lead to proteasomal degradation. Ubiquitination at Lys-254 by XIAP/BIRC4 blocks its ability to bind DNA and induce chromatin degradation, thereby inhibiting its ability to induce cell death By similarity.
Sequence similarities	Belongs to the FAD-dependent oxidoreductase family.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Membrane Mitochondrion Mitochondrion inner membrane Nucleus
Domain	Transit peptide
Ligand	DNA-binding FAD Flavoprotein
Molecular function	Oxidoreductase
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB apoptotic DNA fragmentation Inferred from genetic interaction PubMed 15703386. Source: MGI apoptotic mitochondrial changes Traceable author statement PubMed 10913597. Source: MGI cell redox homeostasis Inferred from electronic annotation. Source: InterPro intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Inferred from mutant phenotype PubMed 18056262. Source: UniProtKB mitochondrial respiratory chain complex I assembly Inferred from electronic annotation. Source: Compara neuron apoptotic process Inferred from genetic interaction PubMed 15703386. Source: MGI neuron differentiation Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Inferred from direct assay PubMed 18056262. Source: UniProtKB mitochondrial inner membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrial intermembrane space Inferred from sequence or structural similarity. Source: UniProtKB mitochondrial membrane part Inferred from electronic annotation. Source: Compara mitochondrial outer membrane Traceable author statement PubMed 14561754. Source: MGI nucleus Inferred from direct assay PubMed 18056262PubMed 20360685. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW electron-transferring-flavoprotein dehydrogenase activity Traceable author statement PubMed 10913597. Source: MGI flavin adenine dinucleotide binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
H2AFX	P16104	2	EBI-5326677,EBI-494830	From a different organism.
H2afx	P27661	3	EBI-773597,EBI-495621

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 54

54

Mitochondrion By similarity

Propeptide

55 – 101

47

Removed in mature form

PRO_0000401936

Chain

102 – 612

511

Apoptosis-inducing factor 1, mitochondrial

PRO_0000022031

Regions

Nucleotide binding

137 – 141

5

FAD

Nucleotide binding

163 – 164

2

FAD

Nucleotide binding

453 – 454

2

FAD

Region

133 – 482

350

FAD-dependent oxidoreductase

Motif

445 – 450

6

Nuclear localization signal Potential

Sites

Binding site

171

1

FAD

Binding site

176

1

FAD

Binding site

232

1

FAD; via amide nitrogen and carbonyl oxygen

Binding site

284

1

FAD

Binding site

437

1

FAD

Binding site

482

1

FAD; via carbonyl oxygen

Amino acid modifications

Modified residue

267

1

Phosphoserine By similarity

Modified residue

592

1

N6-acetyllysine Ref.4

Cross-link

254

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Mutagenesis

176

1

K → A: Increases catalytic efficiency. Ref.5

Mutagenesis

313

1

E → A: Increases catalytic efficiency 30-fold. Increases affinity for NADH 20-fold. Ref.5

Secondary structure

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612

Helix Strand Turn

Details...

Beta strand

129 – 137

9

Helix

140 – 152

13

Beta strand

157 – 166

10

Helix

172 – 175

4

Helix

177 – 179

3

Helix

186 – 189

4

Beta strand

191 – 193

3

Beta strand

199 – 205

7

Helix

207 – 209

3

Helix

213 – 218

6

Beta strand

223 – 229

7

Beta strand

232 – 236

5

Turn

237 – 240

4

Beta strand

241 – 244

4

Beta strand

249 – 257

9

Beta strand

261 – 263

3

Helix

267 – 270

4

Helix

274 – 277

4

Beta strand

280 – 282

3

Helix

286 – 296

11

Beta strand

300 – 305

6

Helix

309 – 325

17

Beta strand

328 – 332

5

Beta strand

334 – 337

4

Turn

338 – 342

5

Helix

345 – 356

12

Turn

357 – 359

3

Beta strand

361 – 363

3

Beta strand

368 – 374

7

Beta strand

377 – 382

6

Beta strand

387 – 395

9

Beta strand

399 – 401

3

Helix

404 – 406

3

Turn

407 – 410

4

Turn

415 – 417

3

Beta strand

419 – 421

3

Beta strand

426 – 429

4

Beta strand

432 – 434

3

Helix

436 – 438

3

Beta strand

439 – 443

5

Turn

444 – 446

3

Beta strand

447 – 449

3

Helix

454 – 468

15

Turn

469 – 471

3

Beta strand

480 – 486

7

Beta strand

490 – 495

6

Beta strand

503 – 508

6

Helix

516 – 523

8

Helix

528 – 532

5

Beta strand

539 – 542

4

Helix

556 – 558

3

Beta strand

561 – 579

19

Helix

584 – 593

10

Helix

600 – 604

5

Helix

605 – 607

3

Sequences

	Sequence		Length	Mass (Da)
	Q9Z0X1 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: A17EDFD5CF77BB85	FASTA	612	66,765
	10 20 30 40 50 60 MFRCGGLAGA FKQKLVPLVR TVYVQRPKQR NRLPGNLFQQ WRVPLELQMA RQMASSGSSG 70 80 90 100 110 120 GKMDNSVLVL IVGLSTIGAG AYAYKTIKED QKRYNERVMG LGLSPEEKQR RAIASATEGG 130 140 150 160 170 180 SVPQIRAPSH VPFLLIGGGT AAFAAARSIR ARDPGARVLI VSEDPELPYM RPPLSKELWF 190 200 210 220 230 240 SDDPNVTKTL QFRQWNGKER SIYFQPPSFY VSAQDLPNIE NGGVAVLTGK KVVHLDVRGN 250 260 270 280 290 300 MVKLNDGSQI TFEKCLIATG GTPRSLSAID RAGAEVKSRT TLFRKIGDFR ALEKISREVK 310 320 330 340 350 360 SITVIGGGFL GSELACALGR KSQASGIEVI QLFPEKGNMG KILPQYLSNW TMEKVKREGV 370 380 390 400 410 420 KVMPNAIVQS VGVSGGRLLI KLKDGRKVET DHIVTAVGLE PNVELAKTGG LEIDSDFGGF 430 440 450 460 470 480 RVNAELQARS NIWVAGDAAC FYDIKLGRRR VEHHDHAVVS GRLAGENMTG AAKPYWHQSM 490 500 510 520 530 540 FWSDLGPDVG YEAIGLVDSS LPTVGVFAKA TAQDNPKSAT EQSGTGIRSE SETESEASEI 550 560 570 580 590 600 TIPPSAPAVP QVPVEGEDYG KGVIFYLRDK VVVGIVLWNV FNRMPIARKI IKDGEQHEDL 610 NEVAKLFNIH ED

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular characterization of mitochondrial apoptosis-inducing factor." Susin S.A., Lorenzo H.K., Zamzami N., Marzo I., Snow B.E., Brothers G.M., Mangion J., Jacotot E., Costantini P., Loeffler M., Larochette N., Goodlett D.R., Aebersold R., Siderovski D.P., Penninger J.M., Kroemer G. Nature 397:441-446(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF N-TERMINUS, PROTEIN SEQUENCE OF 322-336, FUNCTION, COFACTOR, MASS SPECTROMETRY, SUBCELLULAR LOCATION.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Mammary gland.
[3]	Lubec G., Sunyer B., Chen W.-Q. Submitted (JAN-2009) to UniProtKB Cited for: PROTEIN SEQUENCE OF 378-386, MASS SPECTROMETRY. Strain: OF1. Tissue: Hippocampus.
[4]	"Substrate and functional diversity of lysine acetylation revealed by a proteomics survey." Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T., Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y. Mol. Cell 23:607-618(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-592, MASS SPECTROMETRY. Tissue: Liver.
[5]	"The crystal structure of the mouse apoptosis-inducing factor AIF." Mate M.J., Ortiz-Lombardia M., Boitel B., Haouz A., Tello D., Susin S.A., Penninger J., Kroemer G., Alzari P.M. Nat. Struct. Biol. 9:442-446(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 108-610 IN COMPLEX WITH FAD, NAD-BINDING, MUTAGENESIS OF LYS-176 AND GLU-313.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF100927 mRNA. Translation: AAD16435.1.
BC003292 mRNA. Translation: AAH03292.1.

IPI

IPI00129577.

RefSeq

NP_036149.1. NM_012019.2.

UniGene

Mm.240434.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1GV4	X-ray	2.00	A/B	122-610	[»]
3GD3	X-ray	2.95	A/B/C/D	78-612	[»]
3GD4	X-ray	2.24	A/B	102-612	[»]

ProteinModelPortal

Q9Z0X1.

SMR

Q9Z0X1. Positions 121-610.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9Z0X1. 7 interactions.

STRING

10090.ENSMUSP00000041104.

PTM databases

PhosphoSite

Q9Z0X1.

Proteomic databases

PaxDb

Q9Z0X1.

PRIDE

Q9Z0X1.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000037349; ENSMUSP00000041104; ENSMUSG00000036932.

GeneID

26926.

KEGG

mmu:26926.

Organism-specific databases

CTD

9131.

MGI

MGI:1349419. Aifm1.

Phylogenomic databases

eggNOG

COG0446.

GeneTree

ENSGT00530000063416.

HOGENOM

HOG000264253.

HOVERGEN

HBG053538.

InParanoid

Q9Z0X1.

KO

K04727.

OrthoDB

EOG40S0FD.

Gene expression databases

ArrayExpress

Q9Z0X1.

Bgee

Q9Z0X1.

Genevestigator

Q9Z0X1.

GermOnline

ENSMUSG00000036932. Mus musculus.

Family and domain databases

Gene3D

3.30.390.30. 1 hit.

InterPro

IPR016156. FAD/NAD-linked_Rdtase_dimer.
IPR013027. FAD_pyr_nucl-diS_OxRdtase.
IPR004099. Pyr_nucl-diS_OxRdtase_dimer.
IPR023753. Pyr_nucl-diS_OxRdtase_FAD/NAD.
IPR001327. Pyr_OxRdtase_NAD-bd_dom.
[Graphical view]

Pfam

PF00070. Pyr_redox. 1 hit.
PF07992. Pyr_redox_2. 1 hit.
[Graphical view]

PRINTS

PR00368. FADPNR.

SUPFAM

SSF55424. FAD/NAD-linked_reductase_dimer. 1 hit.

ProtoNet

Search...

Other

ChiTaRS

AIFM1. mouse.

EvolutionaryTrace

Q9Z0X1.

NextBio

304817.

SOURCE

Search...

Entry information

Entry name

AIFM1_MOUSE

Accession

Primary (citable) accession number: Q9Z0X1

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	May 1, 1999
Last modified:	April 3, 2013
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program