AIFM1_RAT
ID AIFM1_RAT Reviewed; 612 AA.
AC Q9JM53; Q548E3;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Apoptosis-inducing factor 1, mitochondrial;
DE EC=1.6.99.- {ECO:0000250|UniProtKB:O95831};
DE AltName: Full=Programmed cell death protein 8;
DE Flags: Precursor;
GN Name=Aifm1; Synonyms=Aif, Pdcd8;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Ohsakaya S., Mihara K.;
RT "Molecular cloning of rat apoptosis-inducing factor (AIF).";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Cerebellum;
RA Cao G., Sheng L., Pei W., Chen J.;
RT "Cloning and characterization of rat apoptosis-inducing factor:
RT implications for DNA fragmentation in cerebral ischemia.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 378-386, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RA Lubec G., Kang S.U., Lubec S.;
RL Submitted (SEP-2007) to UniProtKB.
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-267, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Functions both as NADH oxidoreductase and as regulator of
CC apoptosis (By similarity). In response to apoptotic stimuli, it is
CC released from the mitochondrion intermembrane space into the cytosol
CC and to the nucleus, where it functions as a proapoptotic factor in a
CC caspase-independent pathway. The soluble form (AIFsol) found in the
CC nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of
CC chromosomal DNA (By similarity). Binds to DNA in a sequence-independent
CC manner. Interacts with EIF3G, and thereby inhibits the EIF3 machinery
CC and protein synthesis, and activates caspase-7 to amplify apoptosis.
CC Plays a critical role in caspase-independent, pyknotic cell death in
CC hydrogen peroxide-exposed cells. In contrast, participates in normal
CC mitochondrial metabolism. Plays an important role in the regulation of
CC respiratory chain biogenesis by interacting with CHCHD4 and controlling
CC CHCHD4 mitochondrial import (By similarity).
CC {ECO:0000250|UniProtKB:O95831, ECO:0000250|UniProtKB:Q9Z0X1}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=A + H(+) + NADH = AH2 + NAD(+); Xref=Rhea:RHEA:11356,
CC ChEBI:CHEBI:13193, ChEBI:CHEBI:15378, ChEBI:CHEBI:17499,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000250|UniProtKB:O95831};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:O95831};
CC -!- SUBUNIT: Monomer (oxidized form). Homodimer (reduced form). Upon
CC reduction with NADH, undergoes dimerization and forms tight, long-lived
CC FADH2-NAD charge transfer complexes (CTC) resistant to oxidation. Also
CC dimerizes with isoform 3 preventing its release from mitochondria.
CC Interacts with XIAP/BIRC4. Interacts (via N-terminus) with EIF3G (via
CC C-terminus). Interacts with PRELID1. Interacts with CHCHD4; the
CC interaction increases in presence of NADH.
CC {ECO:0000250|UniProtKB:O95831}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space
CC {ECO:0000250|UniProtKB:O95831}. Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:O95831}. Cytoplasm
CC {ECO:0000250|UniProtKB:O95831}. Nucleus {ECO:0000250|UniProtKB:O95831}.
CC Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:O95831}.
CC Note=Proteolytic cleavage during or just after translocation into the
CC mitochondrial intermembrane space (IMS) results in the formation of an
CC inner-membrane-anchored mature form (AIFmit). During apoptosis, further
CC proteolytic processing leads to a mature form, which is confined to the
CC mitochondrial IMS in a soluble form (AIFsol). AIFsol is released to the
CC cytoplasm in response to specific death signals, and translocated to
CC the nucleus, where it induces nuclear apoptosis. Colocalizes with EIF3G
CC in the nucleus and perinuclear region. {ECO:0000250|UniProtKB:O95831}.
CC -!- PTM: Under normal conditions, a 54-residue N-terminal segment is first
CC proteolytically removed during or just after translocation into the
CC mitochondrial intermembrane space (IMS) by the mitochondrial processing
CC peptidase (MPP) to form the inner-membrane-anchored mature form
CC (AIFmit). During apoptosis, it is further proteolytically processed at
CC amino-acid position 101 leading to the generation of the mature form,
CC which is confined to the mitochondrial IMS in a soluble form (AIFsol).
CC AIFsol is released to the cytoplasm in response to specific death
CC signals, and translocated to the nucleus, where it induces nuclear
CC apoptosis in a caspase-independent manner.
CC {ECO:0000250|UniProtKB:O95831}.
CC -!- PTM: Ubiquitination by XIAP/BIRC4 does not lead to proteasomal
CC degradation. Ubiquitination at Lys-254 by XIAP/BIRC4 blocks its ability
CC to bind DNA and induce chromatin degradation, thereby inhibiting its
CC ability to induce cell death. {ECO:0000250|UniProtKB:O95831}.
CC -!- SIMILARITY: Belongs to the FAD-dependent oxidoreductase family.
CC {ECO:0000305}.
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DR EMBL; AB041723; BAA94745.1; -; mRNA.
DR EMBL; AF375656; AAM46094.1; -; mRNA.
DR EMBL; BC072697; AAH72697.1; -; mRNA.
DR RefSeq; NP_112646.1; NM_031356.1.
DR AlphaFoldDB; Q9JM53; -.
DR SMR; Q9JM53; -.
DR BioGRID; 249749; 2.
DR STRING; 10116.ENSRNOP00000008503; -.
DR iPTMnet; Q9JM53; -.
DR PhosphoSitePlus; Q9JM53; -.
DR jPOST; Q9JM53; -.
DR PaxDb; Q9JM53; -.
DR PRIDE; Q9JM53; -.
DR Ensembl; ENSRNOT00000008503; ENSRNOP00000008503; ENSRNOG00000006067.
DR GeneID; 83533; -.
DR KEGG; rno:83533; -.
DR UCSC; RGD:620817; rat.
DR CTD; 9131; -.
DR RGD; 620817; Aifm1.
DR eggNOG; KOG1346; Eukaryota.
DR GeneTree; ENSGT00940000156455; -.
DR HOGENOM; CLU_003291_5_3_1; -.
DR InParanoid; Q9JM53; -.
DR OMA; EVRYERC; -.
DR OrthoDB; 830428at2759; -.
DR PhylomeDB; Q9JM53; -.
DR TreeFam; TF314028; -.
DR PRO; PR:Q9JM53; -.
DR Proteomes; UP000002494; Chromosome X.
DR Bgee; ENSRNOG00000006067; Expressed in heart and 20 other tissues.
DR ExpressionAtlas; Q9JM53; baseline and differential.
DR Genevisible; Q9JM53; RN.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005758; C:mitochondrial intermembrane space; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0071949; F:FAD binding; ISS:UniProtKB.
DR GO; GO:0016174; F:NAD(P)H oxidase H2O2-forming activity; ISS:UniProtKB.
DR GO; GO:0003954; F:NADH dehydrogenase activity; IEA:RHEA.
DR GO; GO:0016651; F:oxidoreductase activity, acting on NAD(P)H; ISS:UniProtKB.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISO:RGD.
DR GO; GO:1904045; P:cellular response to aldosterone; IEP:RGD.
DR GO; GO:0071392; P:cellular response to estradiol stimulus; IEP:RGD.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEP:RGD.
DR GO; GO:0071732; P:cellular response to nitric oxide; IEP:RGD.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IEP:RGD.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0033108; P:mitochondrial respiratory chain complex assembly; ISS:UniProtKB.
DR GO; GO:0032981; P:mitochondrial respiratory chain complex I assembly; ISO:RGD.
DR GO; GO:0051402; P:neuron apoptotic process; ISO:RGD.
DR GO; GO:0010942; P:positive regulation of cell death; ISO:RGD.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:RGD.
DR GO; GO:0012501; P:programmed cell death; IBA:GO_Central.
DR GO; GO:0045041; P:protein import into mitochondrial intermembrane space; ISS:UniProtKB.
DR GO; GO:1902510; P:regulation of apoptotic DNA fragmentation; ISO:RGD.
DR GO; GO:0002931; P:response to ischemia; IEP:RGD.
DR GO; GO:1902065; P:response to L-glutamate; IEP:RGD.
DR GO; GO:0009636; P:response to toxic substance; IEP:RGD.
DR Gene3D; 3.30.390.30; -; 1.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR029324; AIF_C.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR InterPro; IPR016156; FAD/NAD-linked_Rdtase_dimer_sf.
DR Pfam; PF14721; AIF_C; 1.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR SUPFAM; SSF51905; SSF51905; 2.
DR SUPFAM; SSF55424; SSF55424; 1.
PE 1: Evidence at protein level;
KW Acetylation; Apoptosis; Cytoplasm; Direct protein sequencing; DNA-binding;
KW FAD; Flavoprotein; Isopeptide bond; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; NAD; Nucleus; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Transit peptide; Ubl conjugation.
FT TRANSIT 1..53
FT /note="Mitochondrion"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT PROPEP 54..100
FT /note="Removed in mature form"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT /id="PRO_0000448978"
FT PROPEP 55..101
FT /note="Removed in mature form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000401937"
FT CHAIN 102..612
FT /note="Apoptosis-inducing factor 1, mitochondrial"
FT /id="PRO_0000022032"
FT REGION 133..482
FT /note="FAD-dependent oxidoreductase"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT REGION 512..551
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1..30
FT /note="Mitochondrial localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT MOTIF 62..88
FT /note="Mitochondrial localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT MOTIF 445..450
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 513..540
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 137..141
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 163..164
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 171
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 176
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 195
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 232
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 284
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 307..310
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 335
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 341
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT BINDING 398
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 437
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 452..453
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 453..454
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 482
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 482
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 492
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT BINDING 582
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT MOD_RES 108
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT MOD_RES 115
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT MOD_RES 267
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 370
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT MOD_RES 387
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT MOD_RES 520
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT MOD_RES 523
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95831"
FT MOD_RES 592
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X1"
FT CROSSLNK 254
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O95831"
SQ SEQUENCE 612 AA; 66723 MW; 02ECF24FA7400A86 CRC64;
MFRCGGLAGA FKQKLVPLVR SVCVQRPKQR NRLPGNLFQQ WRVPLELQMA RQMASSGPSG
GKMDNSVLVL IVGLSTIGAG AYAYKTIKED QKRYNERIMG LGLSPEEKQR RAIASAAEGG
SVPPIRVPSH VPFLLIGGGT AAFAAARSIR ARDPGARVLI VSEDPELPYM RPPLSKELWF
SDDPNVTKTL QFRQWNGKER SIYFQPPSFY VSAQDLPHIE NGGVAVLTGK KVVHLDVRGN
MVKLNDGSQI TFEKCLIATG GTPRSLSAID RAGAEVKSRT TLFRKIGDFR ALEKISREVK
SITVIGGGFL GSELACALGR KSQASGIEVI QLFPEKGNMG KILPEYLSNW TMEKVKREGV
KVMPNAIVQS VGVSGGKLLI KLKDGRKVET DHIVTAVGLE PNVELAKTGG LEIDSDFGGF
RVNAELQARS NIWVAGDAAC FYDIKLGRRR VEHHDHAVVS GRLAGENMTG AAKPYWHQSM
FWSDLGPDVG YEAIGLVDSS LPTVGVFAKA TAQDNPKSAT EQSGTGIRSE SETESEASEI
TIPPSDPAVP QVPVEGEDYG KGVIFYLRDK VVVGIVLWNV FNRMPIARKI IKDGEQHEDL
NEVAKLFNIH ED
