AIFM2
entrez
84883
canonical
uniprot
Q9BRQ8
canonical
ensembl
ENSG00000042286
resolver
ensp
ENSP00000312370
resolver
ensp
ENSP00000478931
resolver
genesymbol
AIFM2
resolver
genesymbol_syn
AMID
resolver
genesymbol_syn
PRG3
resolver
hgnc
HGNC:21411
resolver
uniprot
B3KXI0
resolver
uniprot
Q63Z39
resolver
uniprot_entry
FSP1_HUMAN
resolver
uniprot_sec
B3KXI0
resolver
uniprot_sec
Q63Z39
resolver
activity_regulation
ACTIVITY REGULATION: The modification by 4-hydroxy-2-nonenal (HNE) adduction in mitochondria results in loss of the oxidoreductase activity and activation of a novel function in mitochondrial oxidative stress signaling (By similarity). NADH-dependent oxidoreductase activity in response to ferroptotic stress is supported by ALDH7A1, which generates membrane NADH required for AIFM2/FSP1 activity (PubMed:40233740). Inhibited by iFSP1; a species-specific inhibitor that targets the quinone-binding site, and which does not inhibit mouse AIFM2/FSP1 (PubMed:31634899, PubMed:37957306). Inhibited by viFSP1, which targets the NAD(P)H-binding pocket (PubMed:37957306). Strongly inhibited by 3-phenylquinazolinone icFSP1, which promotes AIFM2/FSP1 liquid-liquid phase separation into liquid droplets and relocalization from the membrane into condensates, triggerring ferroptosis (PubMed:37380771). {ECO:0000250|UniProtKB:Q8BUE4, ECO:0000269|PubMed:31634899, ECO:0000269|PubMed:37380771, ECO:0000269|PubMed:37957306, ECO:0000269|PubMed:40233740}.
uniprot
proteins
amino_acid_sequence
MGSQVSVESGALHVVIVGGGFGGIAAASQLQALNVPFMLVDMKDSFHHNVAALRASVETGFAKKTFISYSVTFKDNFRQGLVVGIDLKNQMVLLQGGEALPFSHLILATGSTGPFPGKFNEVSSQQAAIQAYEDMVRQVQRSRFIVVVGGGSAGVEMAAEIKTEYPEKEVTLIHSQVALADKELLPSVRQEVKEILLRKGVQLLLSERVSNLEELPLNEYREYIKVQTDKGTEVATNLVILCTGIKINSSAYRKAFESRLASSGALRVNEHLQVEGHSNVYAIGDCADVRTPKMAYLAGLHANIAVANIVNSVKQRPLQAYKPGALTFLLSMGRNDGVGQISGFYVGRLMVRLTKSRDLFVSTSWKTMRQSPP
uniprot
proteins
ec_number
1.6.5.-
uniprot
proteins
function
FUNCTION: A NAD(P)H-dependent oxidoreductase that acts as a key inhibitor of ferroptosis (PubMed:31634899, PubMed:31634900, PubMed:35922516, PubMed:36788244, PubMed:37957306, PubMed:39881208, PubMed:37739993, PubMed:39160155, PubMed:38414669, PubMed:40233740). At the plasma membrane, catalyzes reduction of coenzyme Q/ubiquinone-10 to ubiquinol-10, a lipophilic radical-trapping antioxidant that prevents lipid oxidative damage and consequently ferroptosis (PubMed:31634899, PubMed:31634900, PubMed:37739993, PubMed:39160155, PubMed:38414669, PubMed:40233740). Acts in parallel to GPX4 to suppress phospholipid peroxidation and ferroptosis (PubMed:31634899, PubMed:31634900). This anti-ferroptotic function is independent of cellular glutathione levels (PubMed:31634899, PubMed:31634900). Also acts as a potent radical-trapping antioxidant by mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle: catalyzes NAD(P)H-dependent reduction of vitamin K (phylloquinone, menaquinone-4 and menadione) to hydroquinone forms (PubMed:35922516, PubMed:36788244). Hydroquinones act as potent radical-trapping antioxidants inhibitor of phospholipid peroxidation and ferroptosis (PubMed:35922516). May play a role in mitochondrial stress signaling (PubMed:26689472). Upon oxidative stress, associates with the lipid peroxidation end product 4-hydroxy-2-nonenal (HNE) forming a lipid adduct devoid of oxidoreductase activity, which then translocates from mitochondria into the nucleus triggering DNA damage and cell death (PubMed:26689472). Capable of DNA binding in a non-sequence specific way (PubMed:15958387). {ECO:0000269|PubMed:15958387, ECO:0000269|PubMed:26689472, ECO:0000269|PubMed:31634899, ECO:0000269|PubMed:31634900, ECO:0000269|PubMed:35922516, ECO:0000269|PubMed:36788244, ECO:0000269|PubMed:37739993, ECO:0000269|PubMed:37957306, ECO:0000269|PubMed:38414669, ECO:0000269|PubMed:39160155, ECO:0000269|PubMed:39881208, ECO:0000269|PubMed:40233740}.
uniprot
proteins
mass_dalton
40527
uniprot
proteins
mutagenesis
MUTAGEN 2; /note="G->A: Impairs N-myristoylation and ferroptosis suppression. Abolished ability to form liquid-liquid phase separation upon binding to 3-phenylquinazolinone icFSP1."; /evidence="ECO:0000269|PubMed:31634899, ECO:0000269|PubMed:37380771"; MUTAGEN 18; /note="G->A: Decreased NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:36788244"; MUTAGEN 20; /note="G->A: Abolished NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:36788244"; MUTAGEN 21; /note="F->A: Decreased NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:36788244"; MUTAGEN 43; /note="K->A: Does not affect ability to inhibit ferroptosis."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 48; /note="H->N: Induces resistance to iFSP1 and viFSP1 inhibitors."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 49; /note="N->A: Reduced oxidoreductase activity."; /evidence="ECO:0000269|PubMed:39160155"; MUTAGEN 82; /note="V->A: Slightly reduced binding to NADH."; /evidence="ECO:0000269|PubMed:38414669"; MUTAGEN 149; /note="G->A: Decreased NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:36788244"; MUTAGEN 151; /note="G->A: Decreased NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:36788244"; MUTAGEN 152; /note="S->A: Strongly reduced binding to 6-hydroxy-FAD cofactor."; /evidence="ECO:0000269|PubMed:39160155"; MUTAGEN 153; /note="A->T: Increased sensitivity to viFSP1 inhibitor."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 156; /note="E->A: Abolished binding to 6-hydroxy-FAD cofactor, leading to impaired NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:31634900, ECO:0000269|PubMed:37739993, ECO:0000269|PubMed:37957306, ECO:0000269|PubMed:38414669, ECO:0000269|PubMed:39160155"; MUTAGEN 160; /note="E->K: Decreased ability to inhibit ferroptosis."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 164; /note="E->A: Does not affect ability to inhibit ferroptosis."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 168; /note="K->Q: Acetylation-mimetic. Results in reduced ubiquitination and increased stability of the protein."; /evidence="ECO:0000269|PubMed:39881208"; MUTAGEN 168; /note="K->R: No acetylation at this site. Results in increased ubiquitination and reduced stability of the protein. Loss of function in negative regulation of ferroptosis."; /evidence="ECO:0000269|PubMed:39881208"; MUTAGEN 174; /note="H->A: Reduced binding to NADH."; /evidence="ECO:0000269|PubMed:38414669"; MUTAGEN 175..176; /note="SQ->AA: Impaired binding with NADPH without affecting binding to NADH; when associated with P-208."; /evidence="ECO:0000269|PubMed:37739993"; MUTAGEN 187; /note="S->A: Abolished ability to form liquid-liquid phase separation upon binding to 3-phenylquinazolinone icFSP1."; /evidence="ECO:0000269|PubMed:37380771"; MUTAGEN 208; /note="R->P: Impaired binding with NADPH without affecting binding to NADH; when associated with 175-A-A-176."; /evidence="ECO:0000269|PubMed:37739993"; MUTAGEN 217; /note="L->A: Abolished ability to form liquid-liquid phase separation upon binding to 3-phenylquinazolinone icFSP1."; /evidence="ECO:0000269|PubMed:37380771"; MUTAGEN 244; /note="G->D: Abolished NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 285; /note="D->N: Abolished NAD(P)H-dependent oxidoreductase activity."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 294; /note="M->I,V: Induces resistance to viFSP1 inhibitor."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 319; /note="Q->A: Abolished ability to form liquid-liquid phase separation upon binding to 3-phenylquinazolinone icFSP1."; /evidence="ECO:0000269|PubMed:37380771"; MUTAGEN 327; /note="T->K,R: Induces resistance to iFSP1 and viFSP1 inhibitors."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 328; /note="F->S: Increased sensitivity to viFSP1 inhibitor."; /evidence="ECO:0000269|PubMed:37957306"; MUTAGEN 355; /note="K->A: Reduced oxidoreductase activity."; /evidence="ECO:0000269|PubMed:39160155"; MUTAGEN 355; /note="K->E,G: Decreased ability to inhibit ferroptosis."; /evidence="ECO:0000269|PubMed:37957306
uniprot
proteins
post_translational_modification
PTM: N-myristoylation at Gly-2 mediates the recruitment to lipid droplets and plasma membrane, enabling its anti-lipid peroxidation activity. {ECO:0000269|PubMed:31634900}.; PTM: Acetylation at Lys-168 prevents AIFM2 ubiquitination and degradation, thereby inhibiting ferroptosis. KAT2B mediates acetylation at Lys-168, while HDAC3 removes it. {ECO:0000269|PubMed:39881208}.; PTM: Ubiquitinated. AIFM2 undergoes 'Lys-29'-ubiquitination and proteasomal degradation, which is inhibited by acetylation at Lys-168. {ECO:0000269|PubMed:39881208}.
uniprot
proteins
protein_family
FAD-dependent oxidoreductase family
uniprot
proteins
pubmed
11980907
uniprot
proteins
pubmed
12135761
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15164054
uniprot
proteins
pubmed
15273740
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15958387
uniprot
proteins
pubmed
17974005
uniprot
proteins
pubmed
20213681
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
25255805
uniprot
proteins
pubmed
26689472
uniprot
proteins
pubmed
31634899
uniprot
proteins
pubmed
31634900
uniprot
proteins
pubmed
35922516
uniprot
proteins
pubmed
36788244
uniprot
proteins
pubmed
37380771
uniprot
proteins
pubmed
37739993
uniprot
proteins
pubmed
37957306
uniprot
proteins
pubmed
38414669
uniprot
proteins
pubmed
39160155
uniprot
proteins
pubmed
39881208
uniprot
proteins
pubmed
40233740
uniprot
proteins
sequence_length
373
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lipid droplet {ECO:0000269|PubMed:31634900}. Cell membrane {ECO:0000269|PubMed:31634900, ECO:0000269|PubMed:40233740}; Lipid-anchor {ECO:0000305}. Cytoplasm {ECO:0000269|PubMed:11980907, ECO:0000269|PubMed:12135761, ECO:0000269|PubMed:26689472}. Mitochondrion membrane {ECO:0000269|PubMed:11980907, ECO:0000269|PubMed:26689472}. Nucleus {ECO:0000269|PubMed:26689472}.
uniprot
proteins
transmembrane_region
TRANSMEM 7..27; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins