FSP1_MOUSE
ID FSP1_MOUSE Reviewed; 373 AA.
AC Q8BUE4; Q8CHZ2;
DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 137.
DE RecName: Full=Ferroptosis suppressor protein 1 {ECO:0000250|UniProtKB:Q9BRQ8};
DE Short=FSP1 {ECO:0000250|UniProtKB:Q9BRQ8};
DE EC=1.6.5.- {ECO:0000250|UniProtKB:Q9BRQ8};
DE AltName: Full=Apoptosis-inducing factor homologous mitochondrion-associated inducer of death {ECO:0000250|UniProtKB:Q9BRQ8};
DE Short=AMID {ECO:0000250|UniProtKB:Q9BRQ8};
DE AltName: Full=p53-responsive gene 3 protein {ECO:0000250|UniProtKB:Q9BRQ8};
GN Name=Aifm2 {ECO:0000312|MGI:MGI:1918611}; Synonyms=Amid;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1] {ECO:0000305, ECO:0000312|EMBL:BAC39497.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:BAC39497.1}, and
RC NOD {ECO:0000312|EMBL:BAE33142.1};
RC TISSUE=Dendritic cell {ECO:0000312|EMBL:BAE33142.1},
RC Mammary gland {ECO:0000312|EMBL:BAC39497.1}, and
RC Melanocyte {ECO:0000312|EMBL:BAE28108.1};
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3] {ECO:0000305, ECO:0000312|EMBL:AAH38129.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:AAH38129.1};
RC TISSUE=Mammary gland {ECO:0000312|EMBL:AAH38129.1};
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] {ECO:0000305}
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=16186796; DOI=10.1038/sj.onc.1209121;
RA Mei J., Webb S., Zhang B., Shu H.-B.;
RT "The p53-inducible apoptotic protein AMID is not required for normal
RT development and tumor suppression.";
RL Oncogene 25:849-856(2006).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH KPNA2
RP AND IPO5, ACTIVITY REGULATION BY 4-HYDROXY-2-NONENAL, SITE, MUTAGENESIS OF
RP HIS-174 AND CYS-187, AND INDUCTION BY DOXORUBICIN.
RX PubMed=26689472; DOI=10.1016/j.freeradbiomed.2015.12.002;
RA Miriyala S., Thippakorn C., Chaiswing L., Xu Y., Noel T., Tovmasyan A.,
RA Batinic-Haberle I., Vander Kooi C.W., Chi W., Latif A.A., Panchatcharam M.,
RA Prachayasittikul V., Butterfield D.A., Vore M., Moscow J., St Clair D.K.;
RT "Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress
RT signaling.";
RL Free Radic. Biol. Med. 91:68-80(2016).
CC -!- FUNCTION: A NAD(P)H-dependent oxidoreductase involved in cellular
CC oxidative stress response. At the plasma membrane, catalyzes reduction
CC of coenzyme Q/ubiquinone-10 to ubiquinol-10, a lipophilic radical-
CC trapping antioxidant that prevents lipid oxidative damage and
CC consequently ferroptosis. Cooperates with GPX4 to suppress phospholipid
CC peroxidation and ferroptosis. This anti-ferroptotic function is
CC independent of cellular glutathione levels (By similarity). May play a
CC role in mitochondrial oxidative signaling (PubMed:26689472). Upon
CC oxidative stress, associates with the lipid peroxidation end product 4-
CC hydroxy-2-nonenal (HNE) forming a lipid adduct devoid of oxidoreductase
CC activity, which then translocates from mitochondria into the nucleus
CC triggering DNA damage and cell death (PubMed:26689472). Capable of DNA
CC binding in a non-sequence specific way (By similarity).
CC {ECO:0000250|UniProtKB:Q9BRQ8, ECO:0000269|PubMed:26689472}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADH + ubiquinone-10 = NAD(+) + ubiquinol-10;
CC Xref=Rhea:RHEA:61984, ChEBI:CHEBI:15378, ChEBI:CHEBI:46245,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:64183;
CC Evidence={ECO:0000250|UniProtKB:Q9BRQ8};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61985;
CC Evidence={ECO:0000250|UniProtKB:Q9BRQ8};
CC -!- COFACTOR:
CC Name=6-hydroxy-FAD; Xref=ChEBI:CHEBI:60470;
CC Evidence={ECO:0000250|UniProtKB:Q9BRQ8};
CC Note=Binds 6-hydroxy-FAD non-covalently.
CC {ECO:0000250|UniProtKB:Q9BRQ8};
CC -!- ACTIVITY REGULATION: The modification by 4-hydroxy-2-nonenal (HNE)
CC adduction in mitochondria results in loss of the oxidoreductase
CC activity and activation of a novel function in mitochondrial oxidative
CC stress signaling. {ECO:0000269|PubMed:26689472}.
CC -!- SUBUNIT: Interacts with importin subunits KPNA2 and IPO5; this
CC interaction likely mediates the translocation into the nucleus upon
CC oxidative stress. {ECO:0000269|PubMed:26689472}.
CC -!- SUBCELLULAR LOCATION: Lipid droplet {ECO:0000250|UniProtKB:Q9BRQ8}.
CC Cell membrane {ECO:0000250|UniProtKB:Q9BRQ8}; Lipid-anchor
CC {ECO:0000305}. Cytoplasm {ECO:0000269|PubMed:26689472}. Mitochondrion
CC membrane {ECO:0000269|PubMed:26689472}. Nucleus
CC {ECO:0000269|PubMed:26689472}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1 {ECO:0000269|PubMed:16141072};
CC IsoId=Q8BUE4-1; Sequence=Displayed;
CC Name=2 {ECO:0000269|PubMed:15489334};
CC IsoId=Q8BUE4-2; Sequence=VSP_052049;
CC -!- TISSUE SPECIFICITY: Detected in most normal tissues as two transcripts
CC of 1.8 and 4.0 kb in length, respectively. Highly expressed in liver,
CC testis, and kidney, and expressed at lower levels in pancreas, spleen,
CC brain and lung (PubMed:16186796). Expressed in heart (at protein level)
CC (PubMed:26689472). {ECO:0000269|PubMed:16186796,
CC ECO:0000269|PubMed:26689472}.
CC -!- INDUCTION: Expression is up-regulated in mouse embryonic fibroblasts by
CC genotoxic reagents 5-fluorouracil and etoposide (PubMed:16186796). Up-
CC regulated in cardiac cells by anticancer drug doxorubicin
CC (PubMed:26689472). {ECO:0000269|PubMed:16186796,
CC ECO:0000269|PubMed:26689472}.
CC -!- PTM: N-myristoylation at Gly-2 mediates the recruitment to lipid
CC droplets and plasma membrane. {ECO:0000250|UniProtKB:Q9BRQ8}.
CC -!- SIMILARITY: Belongs to the FAD-dependent oxidoreductase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION: [Isoform 2]:
CC Sequence=AAH38129.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK085656; BAC39497.1; -; mRNA.
DR EMBL; AK155240; BAE33142.1; -; mRNA.
DR EMBL; AK147741; BAE28108.1; -; mRNA.
DR EMBL; AC153136; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC038129; AAH38129.1; ALT_SEQ; mRNA.
DR CCDS; CCDS23884.1; -. [Q8BUE4-1]
DR CCDS; CCDS48576.1; -. [Q8BUE4-2]
DR RefSeq; NP_001034283.1; NM_001039194.3. [Q8BUE4-1]
DR RefSeq; NP_001271229.1; NM_001284300.1. [Q8BUE4-1]
DR RefSeq; NP_722474.2; NM_153779.2. [Q8BUE4-2]
DR RefSeq; NP_835159.1; NM_178058.4. [Q8BUE4-1]
DR RefSeq; XP_006514187.1; XM_006514124.3. [Q8BUE4-1]
DR AlphaFoldDB; Q8BUE4; -.
DR SMR; Q8BUE4; -.
DR BioGRID; 214662; 4.
DR IntAct; Q8BUE4; 1.
DR STRING; 10090.ENSMUSP00000078998; -.
DR iPTMnet; Q8BUE4; -.
DR PhosphoSitePlus; Q8BUE4; -.
DR EPD; Q8BUE4; -.
DR jPOST; Q8BUE4; -.
DR MaxQB; Q8BUE4; -.
DR PaxDb; Q8BUE4; -.
DR PeptideAtlas; Q8BUE4; -.
DR PRIDE; Q8BUE4; -.
DR ProteomicsDB; 296005; -. [Q8BUE4-1]
DR ProteomicsDB; 296006; -. [Q8BUE4-2]
DR Antibodypedia; 14832; 295 antibodies from 37 providers.
DR DNASU; 71361; -.
DR Ensembl; ENSMUST00000067857; ENSMUSP00000070054; ENSMUSG00000020085. [Q8BUE4-1]
DR Ensembl; ENSMUST00000080099; ENSMUSP00000078998; ENSMUSG00000020085. [Q8BUE4-2]
DR Ensembl; ENSMUST00000099706; ENSMUSP00000097297; ENSMUSG00000020085. [Q8BUE4-1]
DR Ensembl; ENSMUST00000105455; ENSMUSP00000101095; ENSMUSG00000020085. [Q8BUE4-1]
DR GeneID; 71361; -.
DR KEGG; mmu:71361; -.
DR UCSC; uc007fgi.2; mouse. [Q8BUE4-1]
DR UCSC; uc007fgl.1; mouse. [Q8BUE4-2]
DR CTD; 84883; -.
DR MGI; MGI:1918611; Aifm2.
DR VEuPathDB; HostDB:ENSMUSG00000020085; -.
DR eggNOG; KOG1336; Eukaryota.
DR GeneTree; ENSGT00390000004582; -.
DR HOGENOM; CLU_019845_2_1_1; -.
DR InParanoid; Q8BUE4; -.
DR OMA; GDSFRQG; -.
DR OrthoDB; 1463391at2759; -.
DR PhylomeDB; Q8BUE4; -.
DR TreeFam; TF329369; -.
DR BioGRID-ORCS; 71361; 2 hits in 70 CRISPR screens.
DR PRO; PR:Q8BUE4; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q8BUE4; protein.
DR Bgee; ENSMUSG00000020085; Expressed in brown adipose tissue and 180 other tissues.
DR Genevisible; Q8BUE4; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005811; C:lipid droplet; ISO:MGI.
DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0004174; F:electron-transferring-flavoprotein dehydrogenase activity; ISS:UniProtKB.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISS:UniProtKB.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; ISO:MGI.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; ISO:MGI.
DR GO; GO:0110076; P:negative regulation of ferroptosis; ISO:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IMP:UniProtKB.
DR GO; GO:0006743; P:ubiquinone metabolic process; ISO:MGI.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Cytoplasm; DNA-binding; FAD;
KW Flavoprotein; Lipid droplet; Lipoprotein; Membrane; Mitochondrion;
KW Myristate; Nucleus; Oxidoreductase; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q9BRQ8"
FT CHAIN 2..373
FT /note="Ferroptosis suppressor protein 1"
FT /id="PRO_0000238923"
FT TRANSMEM 7..27
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 18..22
FT /ligand="6-hydroxy-FAD"
FT /ligand_id="ChEBI:CHEBI:60470"
FT /evidence="ECO:0000255"
FT BINDING 54
FT /ligand="6-hydroxy-FAD"
FT /ligand_id="ChEBI:CHEBI:60470"
FT /evidence="ECO:0000255"
FT BINDING 82
FT /ligand="6-hydroxy-FAD"
FT /ligand_id="ChEBI:CHEBI:60470"
FT /evidence="ECO:0000255"
FT BINDING 285
FT /ligand="6-hydroxy-FAD"
FT /ligand_id="ChEBI:CHEBI:60470"
FT /evidence="ECO:0000255"
FT SITE 174
FT /note="4-hydroxy-2-nonenal adduction"
FT /evidence="ECO:0000269|PubMed:26689472"
FT SITE 187
FT /note="4-hydroxy-2-nonenal adduction"
FT /evidence="ECO:0000269|PubMed:26689472"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250|UniProtKB:Q9BRQ8"
FT VAR_SEQ 324..373
FT /note="GALTFLLSMGRNDGVGQISGFYVGRLMVRLAKSRDLLISTSWKTMRQSPP
FT -> ETDQPPAALSPALLLWTPARKLTLSEGRINYLQEAGHVRTLQSMAGLFSDRPCVIS
FT L (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_052049"
FT MUTAGEN 174
FT /note="H->R: Impairs the NADH oxidoreductase activity.
FT Impairs mitochondria to nucleus translocation. Confers
FT protection to doxorubicin-induced cytotoxicity."
FT /evidence="ECO:0000269|PubMed:26689472"
FT MUTAGEN 187
FT /note="C->T: Decreases the NADH oxidoreductase activity.
FT Has not effect on mitochondria to nucleus translocation."
FT /evidence="ECO:0000269|PubMed:26689472"
SQ SEQUENCE 373 AA; 40635 MW; A85F02A26C1084BA CRC64;
MGSQVSVDTG AVHVVIVGGG FGGIAAASQL QALNVPFMLV DMKDSFHHNV AALRASVESG
FAKKTFISYS ATFKDNFRQG KVIGIDLKNR MVLLQGGEAL PFSHLILATG STGPFPGKFN
EVSCQQAAIQ AYEDMVKQIQ RSQFIVVVGG GSAGVEMAAE IKTEYPEKEV TLIHSRVPLA
DKELLPCVRQ EVKEILLRKG VQLLLSERVS NLEELPRNEY REYIKVETDK GTEVATNMVI
VCNGIKINSS AYRSAFESRL ASNGALKVNE FLQVEGYSNI YAIGDCADTK EPKMAYHAGL
HANVAVANIV NSMKQRPLKA YKPGALTFLL SMGRNDGVGQ ISGFYVGRLM VRLAKSRDLL
ISTSWKTMRQ SPP
