FZR1_MOUSE
ID FZR1_MOUSE Reviewed; 493 AA.
AC Q9R1K5;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=Fizzy-related protein homolog;
DE Short=Fzr;
DE AltName: Full=Cdh1/Hct1 homolog;
GN Name=Fzr1; Synonyms=Fyr, Fzr;
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 [MRNA].
RX PubMed=12797865; DOI=10.1042/bj20030600;
RA Zhou Y., Ching Y.-P., Ng R.W.M., Jin D.-Y.;
RT "Differential expression, localization and activity of two alternatively
RT spliced isoforms of human APC regulator CDH1.";
RL Biochem. J. 374:349-358(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-36 AND SER-151, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-36; SER-138; SER-146 AND
RP SER-151, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, Spleen, and Testis;
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 [5]
RP DEACETYLATION BY SIRT2, AND INTERACTION WITH SIRT2.
RX PubMed=22014574; DOI=10.1016/j.ccr.2011.09.004;
RA Kim H.S., Vassilopoulos A., Wang R.H., Lahusen T., Xiao Z., Xu X., Li C.,
RA Veenstra T.D., Li B., Yu H., Ji J., Wang X.W., Park S.H., Cha Y.I.,
RA Gius D., Deng C.X.;
RT "SIRT2 maintains genome integrity and suppresses tumorigenesis through
RT regulating APC/C activity.";
RL Cancer Cell 20:487-499(2011).
CC -!- FUNCTION: Substrate-specific adapter for the anaphase promoting
CC complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex.
CC Associates with the APC/C in late mitosis, in replacement of CDC20, and
CC activates the APC/C during anaphase and telophase. The APC/C remains
CC active in degrading substrates to ensure that positive regulators of
CC the cell cycle do not accumulate prematurely. At the G1/S transition
CC FZR1 is phosphorylated, leading to its dissociation from the APC/C.
CC Following DNA damage, it is required for the G2 DNA damage checkpoint:
CC its dephosphorylation and reassociation with the APC/C leads to the
CC ubiquitination of PLK1, preventing entry into mitosis. Acts as an
CC adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for
CC ubiquitination and subsequent proteasomal degradation. Through the
CC regulation of RBBP8/CtIP protein turnover, may play a role in DNA
CC damage response, favoring DNA double-strand repair through error-prone
CC non-homologous end joining (NHEJ) over error-free, RBBP8-mediated
CC homologous recombination (HR). {ECO:0000250|UniProtKB:Q9UM11}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: The unphosphorylated form interacts with APC/C during mitosis.
CC Interacts with NINL. Interacts (in complex with the anaphase promoting
CC complex APC) with MAD2L2; inhibits FZR1-mediated APC/C activation (By
CC similarity). Interacts with SIRT2 (PubMed:22014574). Interacts with
CC USP37. Interacts (via WD repeats) with MAK. Interacts with RBBP8/CtIP;
CC this interaction leads to RBBP8 proteasomal degradation. Interacts with
CC HECW2 (By similarity). Interacts with SASS6; the interaction is
CC regulated by CENATAC and leads to SASS6 proteasomal degradation (By
CC similarity). Interacts (via N-terminus) with CCNF (By similarity).
CC Interacts with CDC6 (By similarity). Interacts with TK1 (via the KEN
CC box) (By similarity). {ECO:0000250|UniProtKB:Q9UM11,
CC ECO:0000269|PubMed:22014574}.
CC -!- INTERACTION:
CC Q9R1K5; Q8VDQ8: Sirt2; NbExp=2; IntAct=EBI-5238560, EBI-911012;
CC -!- PTM: Acetylated. Deacetylated by SIRT2 at Lys-69 and Lys-159;
CC deacetylation enhances the interaction of FZR1 with CDC27, leading to
CC activation of anaphase promoting complex/cyclosome (APC/C).
CC -!- PTM: Phosphorylated during mitosis, probably by maturation promoting
CC factor (MPF), leading to its dissociation of the APC/C. Following DNA
CC damage, it is dephosphorylated by CDC14B in G2 phase, leading to its
CC reassociation with the APC/C, and allowing an efficient G2 DNA damage
CC checkpoint. Phosphorylated by MAK (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the WD repeat CDC20/Fizzy family. {ECO:0000305}.
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DR EMBL; AF083809; AAD52029.1; -; mRNA.
DR EMBL; BC006616; AAH06616.1; -; mRNA.
DR CCDS; CCDS24057.1; -.
DR RefSeq; NP_062731.1; NM_019757.1.
DR AlphaFoldDB; Q9R1K5; -.
DR SMR; Q9R1K5; -.
DR BioGRID; 207933; 194.
DR IntAct; Q9R1K5; 1.
DR STRING; 10090.ENSMUSP00000114203; -.
DR iPTMnet; Q9R1K5; -.
DR PhosphoSitePlus; Q9R1K5; -.
DR EPD; Q9R1K5; -.
DR MaxQB; Q9R1K5; -.
DR PaxDb; Q9R1K5; -.
DR PRIDE; Q9R1K5; -.
DR ProteomicsDB; 267503; -.
DR Antibodypedia; 11031; 355 antibodies from 35 providers.
DR DNASU; 56371; -.
DR Ensembl; ENSMUST00000140901; ENSMUSP00000114203; ENSMUSG00000020235.
DR GeneID; 56371; -.
DR KEGG; mmu:56371; -.
DR UCSC; uc007ght.1; mouse.
DR CTD; 51343; -.
DR MGI; MGI:1926790; Fzr1.
DR VEuPathDB; HostDB:ENSMUSG00000020235; -.
DR eggNOG; KOG0305; Eukaryota.
DR GeneTree; ENSGT00950000183104; -.
DR HOGENOM; CLU_014831_4_2_1; -.
DR InParanoid; Q9R1K5; -.
DR OMA; MDQDYES; -.
DR OrthoDB; 1220675at2759; -.
DR PhylomeDB; Q9R1K5; -.
DR TreeFam; TF101066; -.
DR Reactome; R-MMU-174084; Autodegradation of Cdh1 by Cdh1:APC/C.
DR Reactome; R-MMU-174113; SCF-beta-TrCP mediated degradation of Emi1.
DR Reactome; R-MMU-174178; APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1.
DR Reactome; R-MMU-176407; Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase.
DR Reactome; R-MMU-176408; Regulation of APC/C activators between G1/S and early anaphase.
DR Reactome; R-MMU-176417; Phosphorylation of Emi1.
DR Reactome; R-MMU-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-MMU-68867; Assembly of the pre-replicative complex.
DR Reactome; R-MMU-69017; CDK-mediated phosphorylation and removal of Cdc6.
DR Reactome; R-MMU-69656; Cyclin A:Cdk2-associated events at S phase entry.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 56371; 19 hits in 109 CRISPR screens.
DR ChiTaRS; Fzr1; mouse.
DR PRO; PR:Q9R1K5; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q9R1K5; protein.
DR Bgee; ENSMUSG00000020235; Expressed in dorsal pancreas and 270 other tissues.
DR ExpressionAtlas; Q9R1K5; baseline and differential.
DR Genevisible; Q9R1K5; MM.
DR GO; GO:0005680; C:anaphase-promoting complex; IBA:GO_Central.
DR GO; GO:0031965; C:nuclear membrane; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0010997; F:anaphase-promoting complex binding; IBA:GO_Central.
DR GO; GO:1990757; F:ubiquitin ligase activator activity; IBA:GO_Central.
DR GO; GO:0031145; P:anaphase-promoting complex-dependent catabolic process; ISS:UniProtKB.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0070306; P:lens fiber cell differentiation; IMP:MGI.
DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; ISS:UniProtKB.
DR GO; GO:2000773; P:negative regulation of cellular senescence; IMP:BHF-UCL.
DR GO; GO:1905786; P:positive regulation of anaphase-promoting complex-dependent catabolic process; IBA:GO_Central.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL.
DR GO; GO:1904668; P:positive regulation of ubiquitin protein ligase activity; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; IMP:MGI.
DR GO; GO:0040020; P:regulation of meiotic nuclear division; IDA:MGI.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR024977; Apc4_WD40_dom.
DR InterPro; IPR033010; Cdc20/Fizzy.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR036322; WD40_repeat_dom_sf.
DR PANTHER; PTHR19918; PTHR19918; 1.
DR Pfam; PF12894; ANAPC4_WD40; 1.
DR Pfam; PF00400; WD40; 3.
DR SMART; SM00320; WD40; 6.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 2.
DR PROSITE; PS50082; WD_REPEATS_2; 3.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell cycle; Cell division; DNA damage; DNA repair; Mitosis;
KW Phosphoprotein; Reference proteome; Repeat; Ubl conjugation pathway;
KW WD repeat.
FT CHAIN 1..493
FT /note="Fizzy-related protein homolog"
FT /id="PRO_0000051002"
FT REPEAT 182..222
FT /note="WD 1"
FT REPEAT 227..266
FT /note="WD 2"
FT REPEAT 269..306
FT /note="WD 3"
FT REPEAT 311..350
FT /note="WD 4"
FT REPEAT 353..395
FT /note="WD 5"
FT REPEAT 397..438
FT /note="WD 6"
FT REPEAT 441..480
FT /note="WD 7"
FT REGION 31..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 64..88
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 105..166
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 68..83
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 124..161
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 32
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UM11"
FT MOD_RES 36
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 69
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9UM11"
FT MOD_RES 133
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UM11"
FT MOD_RES 138
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 146
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 151
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 159
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9UM11"
SQ SEQUENCE 493 AA; 54689 MW; B5DC86653D74D9A5 CRC64;
MDQDYERRLL RQIIIQNENT VPCVSEMRRT LTPANSPVSS PSKHGDRFIP SRAGANWSVN
FHRINENEKS PSQNRKAKDA TSDNGKDGLA YSALLKNELL GAGIEKVQDP QTEDRRLQPS
TPEHKGLFTY SLSSKRSSPD DGNDVSPYSL SPVSNKSQKL LRSPRKPTRK ISKIPFKVLD
APELQDDFYL NLVDWSSLNV LSVGLGTCVY LWSACTSQVT RLCDLSVEGD SVTSVGWSER
GNLVAVGTHK GFVQIWDAAA GKKLSMLEGH TARVGALAWN ADQLSSGSRD RMILQRDIRT
PPLQSERRLQ GHRQEVCGLK WSTDHQLLAS GGNDNKLLVW NHSSLSPVQQ YTEHLAAVKA
IAWSPHQHGL LASGGGTADR CIRFWNTLTG QPLQCIDTGS QVCNLAWSKH ANELVSTHGY
SQNQILVWKY PSLTQVAKLT GHSYRVLYLA MSPDGEAIVT GAGDETLRFW NVFSKTRSTK
ESVSVLNLFT RIR
