FZR1_HUMAN
ID FZR1_HUMAN Reviewed; 496 AA.
AC Q9UM11; O75869; Q86U66; Q96NW8; Q9UI96; Q9ULH8; Q9UM10; Q9UNQ1; Q9Y2T8;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2003, sequence version 2.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Fizzy-related protein homolog {ECO:0000305};
DE Short=Fzr;
DE AltName: Full=CDC20-like protein 1;
DE AltName: Full=Cdh1/Hct1 homolog;
DE Short=hCDH1 {ECO:0000303|PubMed:31722219};
GN Name=FZR1 {ECO:0000312|HGNC:HGNC:24824};
GN Synonyms=CDH1 {ECO:0000303|PubMed:14701726}, FYR, FZR, KIAA1242;
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] (ISOFORM 2).
RC TISSUE=Parathyroid adenoma;
RX PubMed=9811605; DOI=10.1016/s0960-9822(07)00510-6;
RA Kramer E.R., Gieffers C., Hoelzl G., Hengstschlaeger M., Peters J.-M.;
RT "Activation of the human anaphase-promoting complex by proteins of the
RT CDC20/Fizzy family.";
RL Curr. Biol. 8:1207-1210(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
RA Kotani S., Oyamatu T., Todokoro K.;
RT "Human homologue of Fizzy-related protein.";
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RA Sudo T., Saya H.;
RT "Identification of a human homolog of the Drosophila fizzy-related
RT protein.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=10574462; DOI=10.1093/dnares/6.5.337;
RA Nagase T., Ishikawa K., Kikuno R., Hirosawa M., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XV. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:337-345(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
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 [9]
RP FUNCTION, AND INTERACTION WITH APC/C.
RX PubMed=9734353; DOI=10.1016/s1097-2765(00)80126-4;
RA Fang G., Yu H., Kirschner M.W.;
RT "Direct binding of CDC20 protein family members activates the anaphase-
RT promoting complex in mitosis and G1.";
RL Mol. Cell 2:163-171(1998).
RN [10]
RP PHOSPHORYLATION.
RX PubMed=10459014; DOI=10.1083/jcb.146.4.791;
RA Kotani S., Tanaka H., Yasuda H., Todokoro K.;
RT "Regulation of APC activity by phosphorylation and regulatory factors.";
RL J. Cell Biol. 146:791-800(1999).
RN [11]
RP INTERACTION WITH MAD2L2.
RX PubMed=11459825; DOI=10.1101/gad.897901;
RA Pfleger C.M., Salic A., Lee E., Kirschner M.W.;
RT "Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel
RT mechanism for regulating Cdh1.";
RL Genes Dev. 15:1759-1764(2001).
RN [12]
RP INTERACTION WITH MAD2L2.
RX PubMed=11459826; DOI=10.1101/gad.898701;
RA Chen J., Fang G.;
RT "MAD2B is an inhibitor of the anaphase-promoting complex.";
RL Genes Dev. 15:1765-1770(2001).
RN [13]
RP INTERACTION WITH TK1, AND FUNCTION.
RX PubMed=14701726; DOI=10.1128/mcb.24.2.514-526.2004;
RA Ke P.Y., Chang Z.F.;
RT "Mitotic degradation of human thymidine kinase 1 is dependent on the
RT anaphase-promoting complex/cyclosome-CDH1-mediated pathway.";
RL Mol. Cell. Biol. 24:514-526(2004).
RN [14]
RP INTERACTION WITH NINL.
RX PubMed=17403670; DOI=10.1074/jbc.m701350200;
RA Wang Y., Zhan Q.;
RT "Cell cycle-dependent expression of centrosomal ninein-like protein in
RT human cells is regulated by the anaphase-promoting complex.";
RL J. Biol. Chem. 282:17712-17719(2007).
RN [15]
RP FUNCTION, PHOSPHORYLATION, DEPHOSPHORYLATION BY CDC14, AND MUTAGENESIS OF
RP SER-40; THR-121; SER-151 AND SER-163.
RX PubMed=18662541; DOI=10.1016/j.cell.2008.05.043;
RA Bassermann F., Frescas D., Guardavaccaro D., Busino L., Peschiaroli A.,
RA Pagano M.;
RT "The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response
RT checkpoint.";
RL Cell 134:256-267(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-32; SER-36; SER-138; SER-146
RP AND SER-151, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-36 AND SER-151, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP FUNCTION, AND INTERACTION WITH USP37.
RX PubMed=21596315; DOI=10.1016/j.molcel.2011.03.027;
RA Huang X., Summers M.K., Pham V., Lill J.R., Liu J., Lee G.,
RA Kirkpatrick D.S., Jackson P.K., Fang G., Dixit V.M.;
RT "Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and
RT promote S phase entry.";
RL Mol. Cell 42:511-523(2011).
RN [20]
RP ACETYLATION AT LYS-69 AND LYS-159, DEACETYLATION BY SIRT2, AND INTERACTION
RP 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).
RN [21]
RP INTERACTION WITH MAK, AND PHOSPHORYLATION.
RX PubMed=21986944; DOI=10.1038/onc.2011.464;
RA Wang L.Y., Kung H.J.;
RT "Male germ cell-associated kinase is overexpressed in prostate cancer cells
RT and causes mitotic defects via deregulation of APC/C(CDH1).";
RL Oncogene 31:2907-2918(2012).
RN [22]
RP INTERACTION WITH HECW2.
RX PubMed=24163370; DOI=10.1074/jbc.m113.472076;
RA Lu L., Hu S., Wei R., Qiu X., Lu K., Fu Y., Li H., Xing G., Li D., Peng R.,
RA He F., Zhang L.;
RT "The HECT type ubiquitin ligase NEDL2 is degraded by anaphase-promoting
RT complex/cyclosome (APC/C)-Cdh1, and its tight regulation maintains the
RT metaphase to anaphase transition.";
RL J. Biol. Chem. 288:35637-35650(2013).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-133; SER-138 AND SER-151, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [24]
RP FUNCTION, AND INTERACTION WITH RBBP8/CTIP.
RX PubMed=25349192; DOI=10.15252/embj.201489017;
RA Lafranchi L., de Boer H.R., de Vries E.G., Ong S.E., Sartori A.A.,
RA van Vugt M.A.;
RT "APC/C(Cdh1) controls CtIP stability during the cell cycle and in response
RT to DNA damage.";
RL EMBO J. 33:2860-2879(2014).
RN [25]
RP INTERACTION WITH CCNF, UBIQUITINATION, AND MUTAGENESIS OF 7-ARG--VAL-14.
RX PubMed=27653696; DOI=10.1016/j.celrep.2016.08.058;
RA Choudhury R., Bonacci T., Arceci A., Lahiri D., Mills C.A., Kernan J.L.,
RA Branigan T.B., DeCaprio J.A., Burke D.J., Emanuele M.J.;
RT "APC/C and SCF(cyclin F) Constitute a Reciprocal Feedback Circuit
RT Controlling S-Phase Entry.";
RL Cell Rep. 16:3359-3372(2016).
RN [26]
RP INTERACTION WITH CDC6.
RX PubMed=26818844; DOI=10.1038/ncomms10530;
RA Walter D., Hoffmann S., Komseli E.S., Rappsilber J., Gorgoulis V.,
RA Soerensen C.S.;
RT "SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-
RT replication.";
RL Nat. Commun. 7:10530-10530(2016).
RN [27]
RP INTERACTION WITH SASS6.
RX PubMed=31722219; DOI=10.1016/j.celrep.2019.10.028;
RA Wang T., Zou Y., Huang N., Teng J., Chen J.;
RT "CCDC84 Acetylation Oscillation Regulates Centrosome Duplication by
RT Modulating HsSAS-6 Degradation.";
RL Cell Rep. 29:2078-2091.e5(2019).
RN [28] {ECO:0007744|PDB:4UI9}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) IN COMPLEX WITH APC/C,
RP SUBUNIT, MUTAGENESIS OF SER-40; ARG-47; ARG-52; THR-121; SER-151 AND
RP SER-163, AND REGION.
RX PubMed=26083744; DOI=10.1038/nature14471;
RA Chang L., Zhang Z., Yang J., McLaughlin S.H., Barford D.;
RT "Atomic structure of the APC/C and its mechanism of protein
RT ubiquitination.";
RL Nature 522:450-454(2015).
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) (PubMed:25349192).
CC {ECO:0000269|PubMed:14701726, ECO:0000269|PubMed:18662541,
CC ECO:0000269|PubMed:21596315, ECO:0000269|PubMed:25349192,
CC ECO:0000269|PubMed:9734353}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: The unphosphorylated form interacts with APC/C during mitosis
CC (PubMed:26083744, PubMed:9734353). Interacts with NINL
CC (PubMed:17403670). Interacts (in complex with the anaphase promoting
CC complex APC) with MAD2L2; inhibits FZR1-mediated APC/C activation
CC (PubMed:11459825, PubMed:11459826). Interacts with SIRT2 and USP37
CC (PubMed:21596315, PubMed:22014574). Interacts (via WD repeats) with MAK
CC (PubMed:21986944). Interacts with RBBP8/CtIP; this interaction leads to
CC RBBP8 proteasomal degradation (PubMed:25349192). Interacts with HECW2
CC (PubMed:24163370). Interacts with SASS6; the interaction is regulated
CC by CENATAC and leads to SASS6 proteasomal degradation
CC (PubMed:31722219). Interacts (via N-terminus) with CCNF
CC (PubMed:27653696). Interacts with CDC6 (PubMed:26818844). Interacts
CC with TK1 (via the KEN box) (PubMed:14701726).
CC {ECO:0000269|PubMed:11459825, ECO:0000269|PubMed:11459826,
CC ECO:0000269|PubMed:14701726, ECO:0000269|PubMed:17403670,
CC ECO:0000269|PubMed:21596315, ECO:0000269|PubMed:21986944,
CC ECO:0000269|PubMed:22014574, ECO:0000269|PubMed:24163370,
CC ECO:0000269|PubMed:25349192, ECO:0000269|PubMed:26083744,
CC ECO:0000269|PubMed:26818844, ECO:0000269|PubMed:27653696,
CC ECO:0000269|PubMed:31722219, ECO:0000269|PubMed:9734353}.
CC -!- INTERACTION:
CC Q9UM11; P30260: CDC27; NbExp=12; IntAct=EBI-724997, EBI-994813;
CC Q9UM11; Q9HAW4: CLSPN; NbExp=4; IntAct=EBI-724997, EBI-1369377;
CC Q9UM11; Q9UI95: MAD2L2; NbExp=2; IntAct=EBI-724997, EBI-77889;
CC Q9UM11; P20794: MAK; NbExp=7; IntAct=EBI-724997, EBI-3911321;
CC Q9UM11; O75943: RAD17; NbExp=2; IntAct=EBI-724997, EBI-968231;
CC Q9UM11; P31350: RRM2; NbExp=2; IntAct=EBI-724997, EBI-2339245;
CC Q9UM11; Q8IXJ6-2: SIRT2; NbExp=2; IntAct=EBI-724997, EBI-5240785;
CC Q9UM11; Q13309: SKP2; NbExp=2; IntAct=EBI-724997, EBI-456291;
CC Q9UM11; P40337: VHL; NbExp=2; IntAct=EBI-724997, EBI-301246;
CC Q9UM11; P40337-1: VHL; NbExp=2; IntAct=EBI-724997, EBI-3504450;
CC Q9UM11; P40337-3: VHL; NbExp=2; IntAct=EBI-724997, EBI-301270;
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus.
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9UM11-1; Sequence=Displayed;
CC Name=2; Synonyms=CDH1alpha, Fzr1;
CC IsoId=Q9UM11-2; Sequence=VSP_008504;
CC Name=3; Synonyms=CDH1beta, Fzr2;
CC IsoId=Q9UM11-3; Sequence=VSP_008503, VSP_008504;
CC -!- TISSUE SPECIFICITY: Isoform 2 is expressed at high levels in heart,
CC liver, spleen and some cancer cell lines whereas isoform 3 is expressed
CC only at low levels in these tissues. {ECO:0000269|PubMed:12797865}.
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 {ECO:0000269|PubMed:22014574}.
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. {ECO:0000269|PubMed:10459014,
CC ECO:0000269|PubMed:18662541, ECO:0000269|PubMed:21986944}.
CC -!- PTM: Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase
CC complex; leading to its degradation by the proteasome.
CC {ECO:0000269|PubMed:27653696}.
CC -!- MISCELLANEOUS: [Isoform 2]: Major. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Minor. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the WD repeat CDC20/Fizzy family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD26623.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the C-terminal part.; Evidence={ECO:0000305};
CC Sequence=AAD26624.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305};
CC Sequence=BAA86556.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF102508; AAD26624.1; ALT_SEQ; mRNA.
DR EMBL; AF102507; AAD26623.1; ALT_SEQ; mRNA.
DR EMBL; AB013462; BAA86954.1; -; mRNA.
DR EMBL; AB013463; BAA86955.1; -; mRNA.
DR EMBL; AF080397; AAF20266.1; -; mRNA.
DR EMBL; AF083810; AAD52030.1; -; mRNA.
DR EMBL; AF433157; AAL28117.1; -; mRNA.
DR EMBL; BT007115; AAP35779.1; -; mRNA.
DR EMBL; AC005787; AAC62835.1; -; Genomic_DNA.
DR EMBL; AC005786; AAC62836.1; -; Genomic_DNA.
DR EMBL; AB033068; BAA86556.1; ALT_INIT; mRNA.
DR EMBL; BC013413; AAH13413.1; -; mRNA.
DR CCDS; CCDS12109.1; -. [Q9UM11-2]
DR CCDS; CCDS45916.1; -. [Q9UM11-1]
DR CCDS; CCDS45917.1; -. [Q9UM11-3]
DR RefSeq; NP_001129669.1; NM_001136197.1. [Q9UM11-3]
DR RefSeq; NP_001129670.1; NM_001136198.1. [Q9UM11-1]
DR RefSeq; NP_057347.2; NM_016263.3. [Q9UM11-2]
DR RefSeq; XP_005259630.1; XM_005259573.4. [Q9UM11-1]
DR PDB; 4UI9; EM; 3.60 A; R=1-496.
DR PDB; 5L9T; EM; 6.40 A; R=1-496.
DR PDB; 5L9U; EM; 6.40 A; R=1-496.
DR PDB; 7QE7; EM; 2.90 A; R=1-496.
DR PDBsum; 4UI9; -.
DR PDBsum; 5L9T; -.
DR PDBsum; 5L9U; -.
DR PDBsum; 7QE7; -.
DR AlphaFoldDB; Q9UM11; -.
DR SMR; Q9UM11; -.
DR BioGRID; 119489; 1130.
DR ComplexPortal; CPX-6088; Anaphase-Promoting complex, FRZ1 variant.
DR DIP; DIP-38700N; -.
DR ELM; Q9UM11; -.
DR IntAct; Q9UM11; 59.
DR MINT; Q9UM11; -.
DR STRING; 9606.ENSP00000378529; -.
DR ChEMBL; CHEMBL4523493; -.
DR GlyGen; Q9UM11; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9UM11; -.
DR PhosphoSitePlus; Q9UM11; -.
DR BioMuta; FZR1; -.
DR DMDM; 37537753; -.
DR EPD; Q9UM11; -.
DR jPOST; Q9UM11; -.
DR MassIVE; Q9UM11; -.
DR MaxQB; Q9UM11; -.
DR PaxDb; Q9UM11; -.
DR PeptideAtlas; Q9UM11; -.
DR PRIDE; Q9UM11; -.
DR ProteomicsDB; 85167; -. [Q9UM11-1]
DR ProteomicsDB; 85168; -. [Q9UM11-2]
DR ProteomicsDB; 85169; -. [Q9UM11-3]
DR Antibodypedia; 11031; 355 antibodies from 35 providers.
DR DNASU; 51343; -.
DR Ensembl; ENST00000313639.8; ENSP00000321800.7; ENSG00000105325.15. [Q9UM11-3]
DR Ensembl; ENST00000395095.7; ENSP00000378529.2; ENSG00000105325.15. [Q9UM11-1]
DR Ensembl; ENST00000441788.7; ENSP00000410369.1; ENSG00000105325.15. [Q9UM11-2]
DR Ensembl; ENST00000652521.1; ENSP00000498659.1; ENSG00000105325.15. [Q9UM11-2]
DR GeneID; 51343; -.
DR KEGG; hsa:51343; -.
DR MANE-Select; ENST00000441788.7; ENSP00000410369.1; NM_016263.4; NP_057347.2. [Q9UM11-2]
DR UCSC; uc002lxt.3; human. [Q9UM11-1]
DR CTD; 51343; -.
DR DisGeNET; 51343; -.
DR GeneCards; FZR1; -.
DR HGNC; HGNC:24824; FZR1.
DR HPA; ENSG00000105325; Low tissue specificity.
DR MIM; 603619; gene.
DR neXtProt; NX_Q9UM11; -.
DR OpenTargets; ENSG00000105325; -.
DR PharmGKB; PA134896003; -.
DR VEuPathDB; HostDB:ENSG00000105325; -.
DR eggNOG; KOG0305; Eukaryota.
DR GeneTree; ENSGT00950000183104; -.
DR HOGENOM; CLU_014831_4_2_1; -.
DR InParanoid; Q9UM11; -.
DR OMA; MDQDYES; -.
DR OrthoDB; 1220675at2759; -.
DR PhylomeDB; Q9UM11; -.
DR TreeFam; TF101066; -.
DR PathwayCommons; Q9UM11; -.
DR Reactome; R-HSA-174084; Autodegradation of Cdh1 by Cdh1:APC/C.
DR Reactome; R-HSA-174113; SCF-beta-TrCP mediated degradation of Emi1.
DR Reactome; R-HSA-174178; APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1.
DR Reactome; R-HSA-176407; Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase.
DR Reactome; R-HSA-176408; Regulation of APC/C activators between G1/S and early anaphase.
DR Reactome; R-HSA-176417; Phosphorylation of Emi1.
DR Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR Reactome; R-HSA-68867; Assembly of the pre-replicative complex.
DR Reactome; R-HSA-69017; CDK-mediated phosphorylation and removal of Cdc6.
DR Reactome; R-HSA-69656; Cyclin A:Cdk2-associated events at S phase entry.
DR Reactome; R-HSA-8853884; Transcriptional Regulation by VENTX.
DR Reactome; R-HSA-9687136; Aberrant regulation of mitotic exit in cancer due to RB1 defects.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q9UM11; -.
DR SIGNOR; Q9UM11; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 51343; 126 hits in 1097 CRISPR screens.
DR ChiTaRS; FZR1; human.
DR GeneWiki; FZR1; -.
DR GenomeRNAi; 51343; -.
DR Pharos; Q9UM11; Tbio.
DR PRO; PR:Q9UM11; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9UM11; protein.
DR Bgee; ENSG00000105325; Expressed in ventricular zone and 174 other tissues.
DR ExpressionAtlas; Q9UM11; baseline and differential.
DR Genevisible; Q9UM11; HS.
DR GO; GO:0005680; C:anaphase-promoting complex; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031965; C:nuclear membrane; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
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; IDA: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; IEA:Ensembl.
DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; IDA:UniProtKB.
DR GO; GO:2000773; P:negative regulation of cellular senescence; ISS: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; IEA:Ensembl.
DR GO; GO:1904668; P:positive regulation of ubiquitin protein ligase activity; IDA:UniProtKB.
DR GO; GO:0070979; P:protein K11-linked ubiquitination; TAS:UniProtKB.
DR GO; GO:0051445; P:regulation of meiotic cell cycle; IC:ComplexPortal.
DR GO; GO:0040020; P:regulation of meiotic nuclear division; IEA:Ensembl.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; IC:ComplexPortal.
DR DisProt; DP01524; -.
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 3D-structure; Acetylation; Alternative splicing; Cell cycle; Cell division;
KW Cytoplasm; DNA damage; DNA repair; Mitosis; Nucleus; Phosphoprotein;
KW Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway;
KW WD repeat.
FT CHAIN 1..496
FT /note="Fizzy-related protein homolog"
FT /id="PRO_0000051001"
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 28..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 47..52
FT /note="Involved in APC/FZR1 E3 ubiquitin-protein ligase
FT complex activity"
FT /evidence="ECO:0000269|PubMed:26083744"
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 28..42
FT /note="Polar residues"
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:0007744|PubMed:18669648"
FT MOD_RES 36
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 69
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:22014574"
FT MOD_RES 133
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 138
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 146
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 151
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 159
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:22014574"
FT VAR_SEQ 130..218
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12797865, ECO:0000303|Ref.2"
FT /id="VSP_008503"
FT VAR_SEQ 481..483
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:10574462,
FT ECO:0000303|PubMed:12797865, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9811605, ECO:0000303|Ref.2,
FT ECO:0000303|Ref.3, ECO:0000303|Ref.6"
FT /id="VSP_008504"
FT MUTAGEN 7..14
FT /note="RRLLRQIV->AAAAAQAA: Reduced interaction with CCNF.
FT Impaired degradation."
FT /evidence="ECO:0000269|PubMed:27653696"
FT MUTAGEN 40
FT /note="S->A: Constitutively active; when associated with A-
FT 121; A-151 and A-163. Does not affect APC/FZR1 E3
FT ubiquitin-protein ligase complex activity; when associated
FT with A-121; A-151 and A-163. Decreases APC/FZR1 E3
FT ubiquitin-protein ligase complex activity; when associated
FT with A-121 and A-151. Decreases APC/FZR1 E3 ubiquitin-
FT protein ligase complex activity; when associated with A-121
FT and A-163."
FT /evidence="ECO:0000269|PubMed:18662541,
FT ECO:0000269|PubMed:26083744"
FT MUTAGEN 47
FT /note="R->A: Inhibits APC/FZR1 E3 ubiquitin-protein ligase
FT complex activity."
FT /evidence="ECO:0000269|PubMed:26083744"
FT MUTAGEN 52
FT /note="R->A: Inhibits APC/FZR1 E3 ubiquitin-protein ligase
FT complex activity."
FT /evidence="ECO:0000269|PubMed:26083744"
FT MUTAGEN 121
FT /note="T->A: Constitutively active; when associated with A-
FT 40; A-151 and A-163. Does not affect APC/FZR1 E3 ubiquitin-
FT protein ligase complex activity; when associated with A-40;
FT A-151 and A-163. Decreases APC/FZR1 E3 ubiquitin-protein
FT ligase complex activity; when associated with A-40 and A-
FT 151. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex
FT activity; when associated with A-40 and A-163. Decreases
FT APC/FZR1 E3 ubiquitin-protein ligase complex activity; when
FT associated with A-151 and A-163."
FT /evidence="ECO:0000269|PubMed:18662541,
FT ECO:0000269|PubMed:26083744"
FT MUTAGEN 151
FT /note="S->A: Constitutively active; when associated with A-
FT 40; A-121 and A-163. Does not affect ubiquitination; when
FT associated with A-40; A-121 and A-163. Decreases
FT ubiquitination; when associated with A-40 and A-163.
FT Decreases ubiquitination; when associated with A-121 and A-
FT 163."
FT /evidence="ECO:0000269|PubMed:18662541,
FT ECO:0000269|PubMed:26083744"
FT MUTAGEN 163
FT /note="S->A: Constitutively active; when associated with A-
FT 40; A-121 and A-151. Does not affect APC/FZR1 E3 ubiquitin-
FT protein ligase complex activity; when associated with A-40;
FT A-121 and A-151. Decreases APC/FZR1 E3 ubiquitin-protein
FT ligase complex activity; when associated with A-40 and A-
FT 121. Decreases APC/FZR1 E3 ubiquitin-protein ligase complex
FT activity; when associated with A-121 and A-151. Decreases
FT ubiquitination; when associated with A-40 and A-151."
FT /evidence="ECO:0000269|PubMed:18662541,
FT ECO:0000269|PubMed:26083744"
FT MUTAGEN 445..447
FT /note="RVL->AVA: Reduced interaction with CCNF."
FT /evidence="ECO:0000269|PubMed:27653696"
FT CONFLICT 259
FT /note="A -> S (in Ref. 3; AAF20266)"
FT /evidence="ECO:0000305"
FT CONFLICT 275
FT /note="G -> W (in Ref. 3; AAF20266)"
FT /evidence="ECO:0000305"
FT CONFLICT 326
FT /note="Q -> H (in Ref. 2; BAA86954/BAA86955)"
FT /evidence="ECO:0000305"
FT CONFLICT 341
FT /note="N -> I (in Ref. 3; AAF20266)"
FT /evidence="ECO:0000305"
FT HELIX 3..16
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 47..49
FT /evidence="ECO:0007829|PDB:7QE7"
FT HELIX 57..62
FT /evidence="ECO:0007829|PDB:7QE7"
FT HELIX 89..99
FT /evidence="ECO:0007829|PDB:7QE7"
FT HELIX 114..117
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:7QE7"
FT HELIX 155..161
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 176..180
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 193..195
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 197..205
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 208..213
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 214..216
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 219..224
FT /evidence="ECO:0007829|PDB:7QE7"
FT HELIX 225..228
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 232..237
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 244..248
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 251..257
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 258..261
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 262..268
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 274..288
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 291..300
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 302..304
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 307..310
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 328..330
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 337..340
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 345..351
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 358..363
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 370..376
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 377..379
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 381..386
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 387..389
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 391..397
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 402..407
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 409..418
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 420..422
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 424..429
FT /evidence="ECO:0007829|PDB:7QE7"
FT TURN 430..433
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 434..440
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 448..451
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 458..461
FT /evidence="ECO:0007829|PDB:7QE7"
FT STRAND 465..470
FT /evidence="ECO:0007829|PDB:7QE7"
SQ SEQUENCE 496 AA; 55179 MW; F6C8FDAF81D8103A CRC64;
MDQDYERRLL RQIVIQNENT MPRVTEMRRT LTPASSPVSS PSKHGDRFIP SRAGANWSVN
FHRINENEKS PSQNRKAKDA TSDNGKDGLA YSALLKNELL GAGIEKVQDP QTEDRRLQPS
TPEKKGLFTY SLSTKRSSPD DGNDVSPYSL SPVSNKSQKL LRSPRKPTRK ISKIPFKVLD
APELQDDFYL NLVDWSSLNV LSVGLGTCVY LWSACTSQVT RLCDLSVEGD SVTSVGWSER
GNLVAVGTHK GFVQIWDAAA GKKLSMLEGH TARVGALAWN AEQLSSGSRD RMILQRDIRT
PPLQSERRLQ GHRQEVCGLK WSTDHQLLAS GGNDNKLLVW NHSSLSPVQQ YTEHLAAVKA
IAWSPHQHGL LASGGGTADR CIRFWNTLTG QPLQCIDTGS QVCNLAWSKH ANELVSTHGY
SQNQILVWKY PSLTQVAKLT GHSYRVLYLA MSPDGEAIVT GAGDETLRFW NVFSKTRSTK
VKWESVSVLN LFTRIR
