FM1AA_MOUSE
ID FM1AA_MOUSE Reviewed; 654 AA.
AC Q9Z2G1; Q3U2C2; Q8C4V3; Q8C6D9; Q8CBW9; Q9DBC6;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Protein fem-1 homolog A-A {ECO:0000305};
DE Short=FEM1a-A {ECO:0000305};
DE AltName: Full=FEM1-alpha-A {ECO:0000305};
DE AltName: Full=Prostaglandin E receptor 4-associated protein {ECO:0000303|PubMed:18270204};
GN Name=Fem1aa {ECO:0000312|MGI:MGI:1335089};
GN Synonyms=Eprap {ECO:0000303|PubMed:18270204},
GN Fem1a {ECO:0000303|PubMed:9828124};
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]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP STAGE.
RC STRAIN=129/Ola;
RX PubMed=9828124; DOI=10.1006/geno.1998.5569;
RA Ventura-Holman T., Seldin M.F., Li W., Maher J.F.;
RT "The murine fem1 gene family: homologs of the Caenorhabditis elegans sex-
RT determination protein FEM-1.";
RL Genomics 54:221-230(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Diencephalon, Liver, Thymus, and Tongue;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Eye, Kidney, and Mammary tumor;
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 FUNCTION, AND INTERACTION WITH NFKB1 AND PTGER4.
RX PubMed=18270204; DOI=10.1074/jbc.m709663200;
RA Minami M., Shimizu K., Okamoto Y., Folco E., Ilasaca M.L., Feinberg M.W.,
RA Aikawa M., Libby P.;
RT "Prostaglandin E receptor type 4-associated protein interacts directly with
RT NF-kappaB1 and attenuates macrophage activation.";
RL J. Biol. Chem. 283:9692-9703(2008).
RN [5]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
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 [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26439841; DOI=10.1371/journal.pgen.1005542;
RA Nakatsuji M., Minami M., Seno H., Yasui M., Komekado H., Higuchi S.,
RA Fujikawa R., Nakanishi Y., Fukuda A., Kawada K., Sakai Y., Kita T.,
RA Libby P., Ikeuchi H., Yokode M., Chiba T.;
RT "EP4 receptor-associated protein in macrophages ameliorates colitis and
RT colitis-associated tumorigenesis.";
RL PLoS Genet. 11:e1005542-e1005542(2015).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27315781; DOI=10.1016/j.ajpath.2016.04.002;
RA Fujikawa R., Higuchi S., Nakatsuji M., Yasui M., Ikedo T., Nagata M.,
RA Yokode M., Minami M.;
RT "EP4 receptor-associated protein in microglia promotes inflammation in the
RT brain.";
RL Am. J. Pathol. 186:1982-1988(2016).
RN [8]
RP PHOSPHORYLATION AT SER-108 AND SER-608, AND MUTAGENESIS OF SER-108 AND
RP SER-608.
RX PubMed=27799315; DOI=10.4049/jimmunol.1502618;
RA Higuchi S., Fujikawa R., Ikedo T., Hayashi K., Yasui M., Nagata M.,
RA Nakatsuji M., Yokode M., Minami M.;
RT "EP4 receptor-associated protein in macrophages protects against bleomycin-
RT induced pulmonary inflammation in mice.";
RL J. Immunol. 197:4436-4443(2016).
RN [9]
RP DISRUPTION PHENOTYPE.
RX PubMed=28624505; DOI=10.1016/j.ajpath.2017.04.010;
RA Fujikawa R., Higuchi S., Nakatsuji M., Yasui M., Ikedo T., Nagata M.,
RA Hayashi K., Yokode M., Minami M.;
RT "Deficiency in EP4 receptor-associated protein ameliorates abnormal
RT anxiety-like behavior and brain inflammation in a mouse model of alzheimer
RT disease.";
RL Am. J. Pathol. 187:1848-1854(2017).
RN [10]
RP DISRUPTION PHENOTYPE.
RX PubMed=28336432; DOI=10.1016/j.bbrc.2017.03.095;
RA Fujikawa R., Higuchi S., Ikedo T., Nagata M., Hayashi K., Yang T.,
RA Miyata T., Yokode M., Minami M.;
RT "Behavioral abnormalities and reduced norepinephrine in EP4 receptor-
RT associated protein (EPRAP)-deficient mice.";
RL Biochem. Biophys. Res. Commun. 486:584-588(2017).
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 (By similarity). The C-degron recognized by the DesCEND
CC pathway is usually a motif of less than ten residues and can be present
CC in full-length proteins, truncated proteins or proteolytically cleaved
CC forms (By similarity). The CRL2(FEM1A) complex specifically recognizes
CC proteins with an arginine at the C-terminus: recognizes and binds
CC 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 (By similarity). Involved in PGE2-EP4-mediated inhibition
CC of inflammation of macrophages via interaction with NFKB1 and PTGER4
CC (PubMed:18270204, PubMed:26439841). Promotes inflammation in brain
CC microglia through MAP2K4/MKK4-mediated signaling (PubMed:27315781).
CC {ECO:0000250|UniProtKB:Q9BSK4, ECO:0000269|PubMed:18270204,
CC ECO:0000269|PubMed:26439841, ECO:0000269|PubMed:27315781}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q9BSK4}.
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 (By similarity). Interacts with PTGER4 (PubMed:18270204).
CC Interacts with NFKB1; the interaction is direct (PubMed:18270204).
CC {ECO:0000250|UniProtKB:Q9BSK4, ECO:0000269|PubMed:18270204}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:19406122}.
CC Cytoplasm {ECO:0000250|UniProtKB:Q9BSK4}.
CC -!- TISSUE SPECIFICITY: Preferentially expressed in cardiac muscle, brain
CC and liver (at protein level) (PubMed:9828124, PubMed:19406122). Also
CC expressed in skeletal muscle (PubMed:9828124).
CC {ECO:0000269|PubMed:19406122, ECO:0000269|PubMed:9828124}.
CC -!- DEVELOPMENTAL STAGE: Expressed during embryogenesis.
CC {ECO:0000269|PubMed:9828124}.
CC -!- INDUCTION: Up-regulated in ischemic hearts.
CC {ECO:0000269|PubMed:19406122}.
CC -!- PTM: Phosphorylated; highly phosphorylated in myoblasts and myotubes
CC (PubMed:19406122). Phosphorylation at Ser-108 and Ser-608 promote PGE2-
CC EP4-mediated inhibition of inflammation (PubMed:27799315).
CC Dephosphorylated by protein phosphatase 2A (PP2A) (PubMed:27799315).
CC {ECO:0000269|PubMed:19406122, ECO:0000269|PubMed:27799315}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype in normal conditions: mice
CC are fertile and develop normally without any apparent malformation
CC (PubMed:26439841, PubMed:27315781). In mice model of chronic
CC inflammation, mice develop more severe colitis induced by dextran
CC sodium sulfate (DSS) (PubMed:26439841). Mice display less microglial
CC accumulation; decreased microglial activation is observed in the brain
CC after systemic lipopolysaccharide administration (PubMed:27315781).
CC Mice also show behavioral abnormalities, possibly caused by monoamine
CC deficits (PubMed:28336432). Mice display reduced anxiety-like behavior
CC and brain inflammation in a model of Alzheimer disease
CC (PubMed:28624505). {ECO:0000269|PubMed:26439841,
CC ECO:0000269|PubMed:27315781, ECO:0000269|PubMed:28336432,
CC ECO:0000269|PubMed:28624505}.
CC -!- SIMILARITY: Belongs to the fem-1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC28699.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF064447; AAC82372.1; -; Genomic_DNA.
DR EMBL; AK005041; BAB23768.1; -; mRNA.
DR EMBL; AK034412; BAC28699.1; ALT_FRAME; mRNA.
DR EMBL; AK075860; BAC36011.1; -; mRNA.
DR EMBL; AK080978; BAC38102.1; -; mRNA.
DR EMBL; AK147879; BAE28199.1; -; mRNA.
DR EMBL; AK155363; BAE33219.1; -; mRNA.
DR EMBL; BC009161; AAH09161.1; -; mRNA.
DR EMBL; BC054382; AAH54382.1; -; mRNA.
DR EMBL; BC110669; AAI10670.1; -; mRNA.
DR CCDS; CCDS28899.1; -.
DR RefSeq; NP_034322.3; NM_010192.4.
DR AlphaFoldDB; Q9Z2G1; -.
DR SMR; Q9Z2G1; -.
DR BioGRID; 199630; 2.
DR STRING; 10090.ENSMUSP00000057996; -.
DR iPTMnet; Q9Z2G1; -.
DR PhosphoSitePlus; Q9Z2G1; -.
DR EPD; Q9Z2G1; -.
DR MaxQB; Q9Z2G1; -.
DR PaxDb; Q9Z2G1; -.
DR PRIDE; Q9Z2G1; -.
DR ProteomicsDB; 267367; -.
DR DNASU; 14154; -.
DR Ensembl; ENSMUST00000060253; ENSMUSP00000057996; ENSMUSG00000043683.
DR GeneID; 14154; -.
DR KEGG; mmu:14154; -.
DR UCSC; uc008dbk.2; mouse.
DR CTD; 55527; -.
DR MGI; MGI:1335089; Fem1a.
DR VEuPathDB; HostDB:ENSMUSG00000043683; -.
DR eggNOG; KOG0508; Eukaryota.
DR GeneTree; ENSGT00940000161210; -.
DR HOGENOM; CLU_020042_2_0_1; -.
DR InParanoid; Q9Z2G1; -.
DR OMA; DHCGARV; -.
DR OrthoDB; 252380at2759; -.
DR PhylomeDB; Q9Z2G1; -.
DR TreeFam; TF351376; -.
DR Reactome; R-MMU-8951664; Neddylation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 14154; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Fem1a; mouse.
DR PRO; PR:Q9Z2G1; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q9Z2G1; protein.
DR Bgee; ENSMUSG00000043683; Expressed in extensor digitorum longus and 241 other tissues.
DR Genevisible; Q9Z2G1; MM.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; ISS:UniProtKB.
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; ISO:MGI.
DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IGI:MGI.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IDA:MGI.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP: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; ISS: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; 3.
DR Pfam; PF13857; Ank_5; 1.
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..654
FT /note="Protein fem-1 homolog A-A"
FT /id="PRO_0000324526"
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 283..317
FT /note="TPR 1"
FT REPEAT 375..408
FT /note="TPR 2"
FT REPEAT 519..561
FT /note="ANK 8"
FT REPEAT 565..594
FT /note="ANK 9"
FT REGION 242..265
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 242..262
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 108
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:27799315"
FT MOD_RES 608
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:27799315"
FT MUTAGEN 108
FT /note="S->A: Decreased ability to promote PGE2-EP4-mediated
FT inhibition of inflammation; when associated with A-608."
FT /evidence="ECO:0000269|PubMed:27799315"
FT MUTAGEN 608
FT /note="S->A: Decreased ability to promote PGE2-EP4-mediated
FT inhibition of inflammation; when associated with A-108."
FT /evidence="ECO:0000269|PubMed:27799315"
FT CONFLICT 27
FT /note="G -> E (in Ref. 2; BAE33219)"
FT /evidence="ECO:0000305"
FT CONFLICT 55
FT /note="D -> E (in Ref. 2; BAC28699)"
FT /evidence="ECO:0000305"
FT CONFLICT 111
FT /note="R -> S (in Ref. 2; BAB23768)"
FT /evidence="ECO:0000305"
FT CONFLICT 575
FT /note="Q -> H (in Ref. 2; BAC38102)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 654 AA; 72089 MW; 7A17B38D8E7C63FB CRC64;
MDLHTAVYNA AHDGKLPLLQ KLLAGRGREE LEELLGEVAG GGTPLLIAAR RGHLDVVEYL
VDHCGASVEA SGSVHFDGET IEGAPPLWAA SAAGHLAVVR SLLRRGASVN RTTRTNSTPL
RAACFDGHLD VVRYLVGEHK ADLEVANRHG HTCLMISCYK GHREIARYLL ERGAQVNRRS
AKGNTALHDC AESGSLEILQ LLLGCHARME RDGYGMTPLL AASVTGHTNI VEYLIQEQPG
HEQLSGTELP GEGSSQVAGN HCSTPEEAEP YESCCPTSRE AAVEALELLG ATYVDKKRDL
LGALKHWRRA MELRHQGGGY LPKPEPQQLV LAYDYSREVT TPQELEALIT DPDEMRMQAL
LIRERILGPS HPDTSYYIRY RGAVYADSGN FERCIRLWKY ALDMQQNNLE PLSPMTASSF
LSFAELFSYV LQDRSAKGNL GMQLGFADLM GVLSKGVREV ERALQLPKEP GDSAQFTKAI
AIILHLLYLL EKVECTPSQE HLKHQTVYRL LKCAPRGKNG FTPLHMAVDK ETTNVGRYRV
GVFPSLQVVK VLLDCGADPD SRDFDNNTPL HIAAQNNCPA IMDALIEAGA HMDATNAFKK
TAYELLDSKL LAKSTVQPFN YVTLQCLAAR ALDRNKVPYK GFIPEELEAF IQLH
