FEM1A_HUMAN
ID FEM1A_HUMAN Reviewed; 669 AA.
AC Q9BSK4; B2RDI3; Q711P8; Q9NPN7; Q9NPW8;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 177.
DE RecName: Full=Protein fem-1 homolog A {ECO:0000305};
DE Short=FEM1a {ECO:0000303|PubMed:16254458};
DE AltName: Full=FEM1-alpha {ECO:0000305};
DE AltName: Full=Prostaglandin E receptor 4-associated protein {ECO:0000303|PubMed:16424369};
GN Name=FEM1A {ECO:0000303|PubMed:16254458, ECO:0000312|HGNC:HGNC:16934};
GN Synonyms=EPRAP {ECO:0000303|PubMed:16424369};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP INTERACTION WITH PTGER4.
RX PubMed=16424369; DOI=10.1161/01.res.0000204451.88147.96;
RA Takayama K., Sukhova G.K., Chin M.T., Libby P.;
RT "A novel prostaglandin E receptor 4-associated protein participates in
RT antiinflammatory signaling.";
RL Circ. Res. 98:499-504(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2-669.
RC TISSUE=Skeletal muscle;
RA Ievolella C., Zara I., Millino C., Faulkner G., Lanfranchi G.;
RT "Full length sequencing of an human and murine muscular transcripts
RT (Telethon Italy project B41).";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 470-669.
RG The European IMAGE consortium;
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 576-669.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP INDUCTION.
RX PubMed=16254458; DOI=10.1159/000089261;
RA Ventura-Holman T., Hahn H., Subauste J.S., Maher J.F.;
RT "The Fem1a gene is downregulated in Rhabdomyosarcoma.";
RL Tumor Biol. 26:294-299(2005).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=19406122; DOI=10.1016/j.febslet.2009.04.035;
RA Cambier L., Lacampagne A., Auffray C., Pomies P.;
RT "Fem1a is a mitochondrial protein up-regulated upon ischemia-reperfusion
RT injury.";
RL FEBS Lett. 583:1625-1630(2009).
RN [9]
RP FUNCTION, AND PATHWAY.
RX PubMed=28118078; DOI=10.1080/15384101.2017.1284715;
RA Dankert J.F., Pagan J.K., Starostina N.G., Kipreos E.T., Pagano M.;
RT "FEM1 proteins are ancient regulators of SLBP degradation.";
RL Cell Cycle 16:556-564(2017).
RN [10]
RP FUNCTION, PATHWAY, AND IDENTIFICATION IN A CRL2 E3 UBIQUITIN-PROTEIN LIGASE
RP COMPLEX.
RX PubMed=29779948; DOI=10.1016/j.cell.2018.04.028;
RA Koren I., Timms R.T., Kula T., Xu Q., Li M.Z., Elledge S.J.;
RT "The eukaryotic proteome is shaped by E3 ubiquitin ligases targeting C-
RT terminal degrons.";
RL Cell 173:1622-1635(2018).
RN [11]
RP FUNCTION, AND PATHWAY.
RX PubMed=33398168; DOI=10.1038/s41589-020-00704-3;
RA Chen X., Liao S., Makaros Y., Guo Q., Zhu Z., Krizelman R., Dahan K.,
RA Tu X., Yao X., Koren I., Xu C.;
RT "Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3
RT ligase.";
RL Nat. Chem. Biol. 17:254-262(2021).
RN [12]
RP FUNCTION, AND PATHWAY.
RX PubMed=33398170; DOI=10.1038/s41589-020-00703-4;
RA Yan X., Wang X., Li Y., Zhou M., Li Y., Song L., Mi W., Min J., Dong C.;
RT "Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-
RT degron.";
RL Nat. Chem. Biol. 17:263-271(2021).
RN [13]
RP VARIANT TYR-500.
RX PubMed=16390781; DOI=10.1080/09513590500431458;
RA Maher J.F., Hines R.S., Futterweit W., Crawford S., Lu D., Shen P.,
RA Oefner P., Kazi M., Wilson J.G., Subauste J.S., Cowan B.D.;
RT "FEM1A is a candidate gene for polycystic ovary syndrome.";
RL Gynecol. Endocrinol. 21:330-335(2005).
CC -!- FUNCTION: Substrate-recognition component of a Cul2-RING (CRL2) E3
CC ubiquitin-protein ligase complex of the DesCEND (destruction via C-end
CC degrons) pathway, which recognizes a C-degron located at the extreme C
CC terminus of target proteins, leading to their ubiquitination and
CC degradation (PubMed:29779948, PubMed:33398168, PubMed:33398170). The C-
CC degron recognized by the DesCEND pathway is usually a motif of less
CC than ten residues and can be present in full-length proteins, truncated
CC proteins or proteolytically cleaved forms (PubMed:29779948,
CC PubMed:33398168, PubMed:33398170). The CRL2(FEM1A) complex specifically
CC recognizes proteins with an arginine at the C-terminus: recognizes and
CC binds proteins ending with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-
CC degrons, such as SIL1 or OR51B2, leading to their ubiquitination and
CC degradation (PubMed:33398168, PubMed:33398170). Promotes ubiquitination
CC and degradation of SLBP (PubMed:28118078). Involved in PGE2-EP4-
CC mediated inhibition of inflammation of macrophages via interaction with
CC NFKB1 and PTGER4 (By similarity). Promotes inflammation in brain
CC microglia through MAP2K4/MKK4-mediated signaling (By similarity).
CC {ECO:0000250|UniProtKB:Q9Z2G1, ECO:0000269|PubMed:28118078,
CC ECO:0000269|PubMed:29779948, ECO:0000269|PubMed:33398168,
CC ECO:0000269|PubMed:33398170}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:28118078, ECO:0000269|PubMed:29779948,
CC ECO:0000269|PubMed:33398168, ECO:0000269|PubMed:33398170}.
CC -!- SUBUNIT: Component of a CRL2 E3 ubiquitin-protein ligase complex, also
CC named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of
CC CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter
CC FEM1A (PubMed:29779948). Interacts with PTGER4 (PubMed:16424369).
CC Interacts with NFKB1; the interaction is direct (By similarity).
CC {ECO:0000250|UniProtKB:Q9Z2G1, ECO:0000269|PubMed:16424369,
CC ECO:0000269|PubMed:29779948}.
CC -!- INTERACTION:
CC Q9BSK4; P09110: ACAA1; NbExp=3; IntAct=EBI-2515349, EBI-3926709;
CC Q9BSK4; A6NEM1: GOLGA6L9; NbExp=3; IntAct=EBI-2515349, EBI-5916454;
CC Q9BSK4; Q0VD86: INCA1; NbExp=3; IntAct=EBI-2515349, EBI-6509505;
CC Q9BSK4; Q9BVG8-5: KIFC3; NbExp=3; IntAct=EBI-2515349, EBI-14069005;
CC Q9BSK4; Q9UDY8-2: MALT1; NbExp=3; IntAct=EBI-2515349, EBI-12056869;
CC Q9BSK4; Q5VTT5-2: MYOM3; NbExp=3; IntAct=EBI-2515349, EBI-12247808;
CC Q9BSK4; O14561: NDUFAB1; NbExp=3; IntAct=EBI-2515349, EBI-1246261;
CC Q9BSK4; Q8N543: OGFOD1; NbExp=3; IntAct=EBI-2515349, EBI-13327083;
CC Q9BSK4; Q9NZC7-5: WWOX; NbExp=3; IntAct=EBI-2515349, EBI-12040603;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:19406122}.
CC Cytoplasm {ECO:0000305|PubMed:16424369}.
CC -!- TISSUE SPECIFICITY: Present in macrophages derived from peripheral
CC blood monocytes. Also present in atheromata (at protein level).
CC {ECO:0000269|PubMed:16424369}.
CC -!- INDUCTION: Frequently down-regulated in rhabdomyosarcoma.
CC {ECO:0000269|PubMed:16254458}.
CC -!- PTM: Phosphorylated; highly phosphorylated in myoblasts and myotubes.
CC Phosphorylation at Ser-108 promotes PGE2-EP4-mediated inhibition of
CC inflammation. Dephosphorylated by protein phosphatase 2A (PP2A).
CC {ECO:0000250|UniProtKB:Q9Z2G1}.
CC -!- SIMILARITY: Belongs to the fem-1 family. {ECO:0000305}.
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DR EMBL; AY356352; AAR10439.1; -; mRNA.
DR EMBL; AK315554; BAG37930.1; -; mRNA.
DR EMBL; BC004988; AAH04988.1; -; mRNA.
DR EMBL; AJ311359; CAC85342.1; -; mRNA.
DR EMBL; AL365408; CAB96952.1; -; mRNA.
DR EMBL; AL359589; CAB94875.1; -; mRNA.
DR EMBL; CR749732; CAH18491.1; -; mRNA.
DR CCDS; CCDS12135.1; -.
DR PIR; T50619; T50619.
DR RefSeq; NP_061178.1; NM_018708.2.
DR AlphaFoldDB; Q9BSK4; -.
DR SMR; Q9BSK4; -.
DR BioGRID; 120699; 104.
DR IntAct; Q9BSK4; 21.
DR STRING; 9606.ENSP00000269856; -.
DR iPTMnet; Q9BSK4; -.
DR PhosphoSitePlus; Q9BSK4; -.
DR BioMuta; FEM1A; -.
DR DMDM; 74752305; -.
DR EPD; Q9BSK4; -.
DR jPOST; Q9BSK4; -.
DR MassIVE; Q9BSK4; -.
DR MaxQB; Q9BSK4; -.
DR PaxDb; Q9BSK4; -.
DR PeptideAtlas; Q9BSK4; -.
DR PRIDE; Q9BSK4; -.
DR ProteomicsDB; 78912; -.
DR Antibodypedia; 11533; 150 antibodies from 30 providers.
DR DNASU; 55527; -.
DR Ensembl; ENST00000269856.5; ENSP00000269856.3; ENSG00000141965.5.
DR GeneID; 55527; -.
DR KEGG; hsa:55527; -.
DR MANE-Select; ENST00000269856.5; ENSP00000269856.3; NM_018708.3; NP_061178.1.
DR UCSC; uc002mbf.4; human.
DR CTD; 55527; -.
DR DisGeNET; 55527; -.
DR GeneCards; FEM1A; -.
DR HGNC; HGNC:16934; FEM1A.
DR HPA; ENSG00000141965; Group enriched (skeletal muscle, tongue).
DR MIM; 613538; gene.
DR neXtProt; NX_Q9BSK4; -.
DR OpenTargets; ENSG00000141965; -.
DR PharmGKB; PA134940973; -.
DR VEuPathDB; HostDB:ENSG00000141965; -.
DR eggNOG; KOG0508; Eukaryota.
DR GeneTree; ENSGT00940000161210; -.
DR HOGENOM; CLU_020042_2_0_1; -.
DR InParanoid; Q9BSK4; -.
DR OMA; DHCGARV; -.
DR OrthoDB; 252380at2759; -.
DR PhylomeDB; Q9BSK4; -.
DR TreeFam; TF351376; -.
DR PathwayCommons; Q9BSK4; -.
DR Reactome; R-HSA-8951664; Neddylation.
DR SignaLink; Q9BSK4; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 55527; 41 hits in 1083 CRISPR screens.
DR ChiTaRS; FEM1A; human.
DR GenomeRNAi; 55527; -.
DR Pharos; Q9BSK4; Tbio.
DR PRO; PR:Q9BSK4; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9BSK4; protein.
DR Bgee; ENSG00000141965; Expressed in skeletal muscle tissue of rectus abdominis and 188 other tissues.
DR Genevisible; Q9BSK4; HS.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IBA:GO_Central.
DR GO; GO:0031867; F:EP4 subtype prostaglandin E2 receptor binding; IPI:UniProtKB.
DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; IDA:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0051438; P:regulation of ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0140627; P:ubiquitin-dependent protein catabolic process via the C-end degron rule pathway; IDA:UniProtKB.
DR Gene3D; 1.25.40.10; -; 1.
DR Gene3D; 1.25.40.20; -; 3.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR011990; TPR-like_helical_dom_sf.
DR Pfam; PF12796; Ank_2; 4.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 9.
DR SUPFAM; SSF48403; SSF48403; 2.
DR SUPFAM; SSF48452; SSF48452; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 2.
DR PROSITE; PS50088; ANK_REPEAT; 7.
PE 1: Evidence at protein level;
KW ANK repeat; Cytoplasm; Mitochondrion; Phosphoprotein; Reference proteome;
KW Repeat; TPR repeat; Ubl conjugation pathway.
FT CHAIN 1..669
FT /note="Protein fem-1 homolog A"
FT /id="PRO_0000324525"
FT REPEAT 2..31
FT /note="ANK 1"
FT REPEAT 40..70
FT /note="ANK 2"
FT REPEAT 82..111
FT /note="ANK 3"
FT REPEAT 115..145
FT /note="ANK 4"
FT REPEAT 149..178
FT /note="ANK 5"
FT REPEAT 182..211
FT /note="ANK 6"
FT REPEAT 214..243
FT /note="ANK 7"
FT REPEAT 298..332
FT /note="TPR 1"
FT REPEAT 390..423
FT /note="TPR 2"
FT REPEAT 534..576
FT /note="ANK 8"
FT REPEAT 580..609
FT /note="ANK 9"
FT REGION 240..278
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 254..278
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 108
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2G1"
FT VARIANT 500
FT /note="H -> Y (found in a patient with polycystic ovary
FT syndrome; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:16390781"
FT /id="VAR_039809"
SQ SEQUENCE 669 AA; 73639 MW; FF0010DE5207D48F CRC64;
MDLRTAVYNA ARDGKLQLLQ KLLSGRSREE LDELTGEVAG GGTPLLIAAR YGHLDVVEYL
VDRCGASVEA GGSVHFDGET IEGAPPLWAA SAAGHLDVVR SLLRRGASVN RTTRTNSTPL
RAACFDGHLE VVRYLVGEHQ ADLEVANRHG HTCLMISCYK GHREIARYLL EQGAQVNRRS
AKGNTALHDC AESGSLEILQ LLLGCKARME RDGYGMTPLL AASVTGHTNI VEYLIQEQPG
QEQVAGGEAQ PGLPQEDPST SQGCAQPQGA PCCSSSPEEP LNGESYESCC PTSREAAVEA
LELLGATYVD KKRDLLGALK HWRRAMELRH QGGEYLPKPE PPQLVLAYDY SREVNTTEEL
EALITDPDEM RMQALLIRER ILGPSHPDTS YYIRYRGAVY ADSGNFERCI RLWKYALDMQ
QSNLEPLSPM TASSFLSFAE LFSYVLQDRA AKGSLGTQIG FADLMGVLTK GVREVERALQ
LPREPGDSAQ FTKALAIILH LLYLLEKVEC TPSQEHLKHQ TVYRLLKCAP RGKNGFTPLH
MAVDKDTTNV GRYPVGRFPS LHVVKVLLDC GADPDSRDFD NNTPLHIAAQ NNCPAIMNAL
IEAGAHMDAT NAFKKTAYEL LDEKLLARGT MQPFNYVTLQ CLAARALDKN KIPYKGFIPE
DLEAFIELH
