ID FBXL3_MOUSE Reviewed; 428 AA.
AC Q8C4V4; Q80V32; Q8K1W0; Q9QXW1;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 27-MAR-2024, entry version 153.
DE RecName: Full=F-box/LRR-repeat protein 3;
DE AltName: Full=F-box and leucine-rich repeat protein 3A;
DE AltName: Full=F-box/LRR-repeat protein 3A;
DE AltName: Full=Protein after-hours;
DE AltName: Full=Protein overtime;
GN Name=Fbxl3; Synonyms=Afh, Fbl3a, Fbxl3a, Ovtm;
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] (ISOFORM 1).
RX PubMed=10531037; DOI=10.1016/s0960-9822(00)80021-4;
RA Winston J.T., Koepp D.M., Zhu C., Elledge S.J., Harper J.W.;
RT "A family of mammalian F-box proteins.";
RL Curr. Biol. 9:1180-1182(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Adrenal gland;
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 GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=FVB/N-3; TISSUE=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 [5]
RP FUNCTION IN CIRCADIAN CLOCK, TISSUE SPECIFICITY, INTERACTION WITH CRY1 AND
RP CRY2, AND MUTAGENESIS OF ILE-364.
RX PubMed=17462724; DOI=10.1016/j.cell.2007.04.030;
RA Siepka S.M., Yoo S.H., Park J., Song W., Kumar V., Hu Y., Lee C.,
RA Takahashi J.S.;
RT "Circadian mutant Overtime reveals F-box protein FBXL3 regulation of
RT cryptochrome and period gene expression.";
RL Cell 129:1011-1023(2007).
RN [6]
RP FUNCTION IN CIRCADIAN CLOCK, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP CYS-358.
RX PubMed=17463252; DOI=10.1126/science.1141138;
RA Godinho S.I., Maywood E.S., Shaw L., Tucci V., Barnard A.R., Busino L.,
RA Pagano M., Kendall R., Quwailid M.M., Romero M.R., O'neill J.,
RA Chesham J.E., Brooker D., Lalanne Z., Hastings M.H., Nolan P.M.;
RT "The after-hours mutant reveals a role for Fbxl3 in determining mammalian
RT circadian period.";
RL Science 316:897-900(2007).
RN [7]
RP FUNCTION IN CIRCADIAN CLOCK, INTERACTION WITH CRY1, AND TISSUE SPECIFICITY.
RX PubMed=18953409; DOI=10.1371/journal.pone.0003530;
RA Dardente H., Mendoza J., Fustin J.M., Challet E., Hazlerigg D.G.;
RT "Implication of the F-Box Protein FBXL21 in circadian pacemaker function in
RT mammals.";
RL PLoS ONE 3:E3530-E3530(2008).
RN [8]
RP FUNCTION IN CIRCADIAN CLOCK, SUBCELLULAR LOCATION, INTERACTION WITH CRY1
RP AND CRY2, IDENTIFICATION IN A SCF PROTEIN LIGASE COMPLEX, AND MUTAGENESIS
RP OF GLY-143.
RX PubMed=23452855; DOI=10.1016/j.cell.2013.01.055;
RA Yoo S.H., Mohawk J.A., Siepka S.M., Shan Y., Huh S.K., Hong H.K.,
RA Kornblum I., Kumar V., Koike N., Xu M., Nussbaum J., Liu X., Chen Z.,
RA Chen Z.J., Green C.B., Takahashi J.S.;
RT "Competing E3 ubiquitin ligases govern circadian periodicity by degradation
RT of CRY in nucleus and cytoplasm.";
RL Cell 152:1091-1105(2013).
RN [9]
RP FUNCTION IN CIRCADIAN CLOCK, SUBCELLULAR LOCATION, INTERACTION WITH CRY1
RP AND CRY2, IDENTIFICATION IN A SCF PROTEIN LIGASE COMPLEX, DISRUPTION
RP PHENOTYPE, AND MUTAGENESIS OF 22-LYS--ARG-25.
RX PubMed=23452856; DOI=10.1016/j.cell.2013.01.054;
RA Hirano A., Yumimoto K., Tsunematsu R., Matsumoto M., Oyama M.,
RA Kozuka-Hata H., Nakagawa T., Lanjakornsiripan D., Nakayama K.I., Fukada Y.;
RT "FBXL21 regulates oscillation of the circadian clock through ubiquitination
RT and stabilization of cryptochromes.";
RL Cell 152:1106-1118(2013).
RN [10]
RP FUNCTION IN CIRCADIAN CLOCK.
RX PubMed=23616524; DOI=10.1523/jneurosci.4950-12.2013;
RA Anand S.N., Maywood E.S., Chesham J.E., Joynson G., Banks G.T.,
RA Hastings M.H., Nolan P.M.;
RT "Distinct and separable roles for endogenous CRY1 and CRY2 within the
RT circadian molecular clockwork of the suprachiasmatic nucleus, as revealed
RT by the Fbxl3(Afh) mutation.";
RL J. Neurosci. 33:7145-7153(2013).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH HDAC3.
RX PubMed=26776516; DOI=10.1016/j.celrep.2015.12.076;
RA Shi G., Xie P., Qu Z., Zhang Z., Dong Z., An Y., Xing L., Liu Z., Dong Y.,
RA Xu G., Yang L., Liu Y., Xu Y.;
RT "Distinct roles of HDAC3 in the core circadian negative feedback loop are
RT critical for clock function.";
RL Cell Rep. 14:823-834(2016).
RN [12]
RP DEGRADATION VIA AUTOPHAGY.
RX PubMed=29937374; DOI=10.1016/j.cmet.2018.05.023;
RA Toledo M., Batista-Gonzalez A., Merheb E., Aoun M.L., Tarabra E., Feng D.,
RA Sarparanta J., Merlo P., Botre F., Schwartz G.J., Pessin J.E., Singh R.;
RT "Autophagy regulates the liver clock and glucose metabolism by degrading
RT CRY1.";
RL Cell Metab. 28:268-281(2018).
RN [13]
RP INTERACTION WITH CRY1 AND KDM8.
RX PubMed=30500822; DOI=10.1371/journal.pbio.2006145;
RA Saran A.R., Kalinowska D., Oh S., Janknecht R., DiTacchio L.;
RT "JMJD5 links CRY1 function and proteasomal degradation.";
RL PLoS Biol. 16:E2006145-E2006145(2018).
CC -!- FUNCTION: Substrate-recognition component of the SCF(FBXL3) E3
CC ubiquitin ligase complex involved in circadian rhythm function. Plays a
CC key role in the maintenance of both the speed and the robustness of the
CC circadian clock oscillation. The SCF(FBXL3) complex mainly acts in the
CC nucleus and mediates ubiquitination and subsequent degradation of CRY1
CC and CRY2. Activity of the SCF(FBXL3) complex is counteracted by the
CC SCF(FBXL21) complex. {ECO:0000269|PubMed:17462724,
CC ECO:0000269|PubMed:17463252, ECO:0000269|PubMed:18953409,
CC ECO:0000269|PubMed:23452855, ECO:0000269|PubMed:23452856,
CC ECO:0000269|PubMed:23616524, ECO:0000269|PubMed:26776516}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase
CC complex SCF(FBXL3) composed of CUL1, SKP1, RBX1 and FBXL3. Interacts
CC with HDAC3 (PubMed:26776516). Interacts with CRY1 and CRY2
CC (phosphorylated) (PubMed:23452856, PubMed:30500822). Interacts with
CC KDM8 (PubMed:30500822). {ECO:0000269|PubMed:17462724,
CC ECO:0000269|PubMed:18953409, ECO:0000269|PubMed:23452855,
CC ECO:0000269|PubMed:23452856, ECO:0000269|PubMed:26776516,
CC ECO:0000269|PubMed:30500822}.
CC -!- INTERACTION:
CC Q8C4V4; P97784: Cry1; NbExp=12; IntAct=EBI-1266589, EBI-1266607;
CC Q8C4V4; Q9R194: Cry2; NbExp=6; IntAct=EBI-1266589, EBI-1266619;
CC Q8C4V4; O54943: Per2; NbExp=2; IntAct=EBI-1266589, EBI-1266779;
CC Q8C4V4; Q13616: CUL1; Xeno; NbExp=3; IntAct=EBI-1266589, EBI-359390;
CC Q8C4V4; P63208: SKP1; Xeno; NbExp=3; IntAct=EBI-1266589, EBI-307486;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26776516}. Cytoplasm.
CC Note=Predominantly nuclear.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8C4V4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8C4V4-2; Sequence=VSP_008414;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed but enriched in brain.
CC Diffusely expressed in the suprachiasmatic nucleus, SCN.
CC {ECO:0000269|PubMed:17462724, ECO:0000269|PubMed:18953409}.
CC -!- PTM: Undergoes autophagy-mediated degradation in the liver in a time-
CC dependent manner. {ECO:0000269|PubMed:29937374}.
CC -!- DISRUPTION PHENOTYPE: Mice show defects in behavioral rhythms with an
CC extremely long-period activity phenotype. The onset of active phase is
CC abnormally delayed from the light-to-dark transition: in constant
CC darkness (DD), mice show significantly longer rhythmic activities. Mice
CC lacking both Fbxl3 and Fbxl21 show an attenuated phenotype in
CC behavioral rhythm compared to Fbxl3-deficient mice; however, they
CC exhibit unstable behavioral rhythms, sometimes eliciting arrhythmicity.
CC {ECO:0000269|PubMed:23452856}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF09131.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH46330.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAM92567.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF176521; AAF09131.1; ALT_INIT; mRNA.
DR EMBL; AK080863; BAC38050.1; -; mRNA.
DR EMBL; AE013600; AAM92567.1; ALT_INIT; Genomic_DNA.
DR EMBL; BC046330; AAH46330.1; ALT_INIT; mRNA.
DR CCDS; CCDS27315.1; -. [Q8C4V4-1]
DR CCDS; CCDS84159.1; -. [Q8C4V4-2]
DR RefSeq; NP_056637.1; NM_015822.2. [Q8C4V4-1]
DR RefSeq; XP_006519302.1; XM_006519239.3.
DR RefSeq; XP_006519303.1; XM_006519240.3.
DR RefSeq; XP_006519304.1; XM_006519241.3.
DR AlphaFoldDB; Q8C4V4; -.
DR SMR; Q8C4V4; -.
DR BioGRID; 206121; 7.
DR IntAct; Q8C4V4; 7.
DR STRING; 10090.ENSMUSP00000022720; -.
DR iPTMnet; Q8C4V4; -.
DR PhosphoSitePlus; Q8C4V4; -.
DR MaxQB; Q8C4V4; -.
DR PaxDb; 10090-ENSMUSP00000022720; -.
DR ProteomicsDB; 270973; -. [Q8C4V4-1]
DR ProteomicsDB; 270974; -. [Q8C4V4-2]
DR Antibodypedia; 24515; 227 antibodies from 32 providers.
DR DNASU; 50789; -.
DR Ensembl; ENSMUST00000022720.15; ENSMUSP00000022720.9; ENSMUSG00000022124.16. [Q8C4V4-1]
DR Ensembl; ENSMUST00000132004.8; ENSMUSP00000115843.2; ENSMUSG00000022124.16. [Q8C4V4-2]
DR Ensembl; ENSMUST00000145693.8; ENSMUSP00000116044.2; ENSMUSG00000022124.16. [Q8C4V4-1]
DR GeneID; 50789; -.
DR KEGG; mmu:50789; -.
DR UCSC; uc007uwh.1; mouse. [Q8C4V4-2]
DR UCSC; uc007uwi.1; mouse. [Q8C4V4-1]
DR AGR; MGI:1354702; -.
DR CTD; 26224; -.
DR MGI; MGI:1354702; Fbxl3.
DR VEuPathDB; HostDB:ENSMUSG00000022124; -.
DR eggNOG; KOG1947; Eukaryota.
DR GeneTree; ENSGT00940000159395; -.
DR HOGENOM; CLU_033637_0_0_1; -.
DR InParanoid; Q8C4V4; -.
DR OMA; HFHTIEK; -.
DR OrthoDB; 2876716at2759; -.
DR PhylomeDB; Q8C4V4; -.
DR TreeFam; TF352583; -.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 50789; 4 hits in 61 CRISPR screens.
DR ChiTaRS; Fbxl3; mouse.
DR PRO; PR:Q8C4V4; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q8C4V4; Protein.
DR Bgee; ENSMUSG00000022124; Expressed in aortic valve and 253 other cell types or tissues.
DR ExpressionAtlas; Q8C4V4; baseline and differential.
DR Genevisible; Q8C4V4; MM.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0019005; C:SCF ubiquitin ligase complex; ISS:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IEA:Ensembl.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IMP:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0031648; P:protein destabilization; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR CDD; cd22178; F-box_FBXL3; 1.
DR Gene3D; 1.20.1280.50; -; 1.
DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1.
DR InterPro; IPR036047; F-box-like_dom_sf.
DR InterPro; IPR001810; F-box_dom.
DR InterPro; IPR032675; LRR_dom_sf.
DR PANTHER; PTHR10224; ES1 PROTEIN HOMOLOG, MITOCHONDRIAL; 1.
DR PANTHER; PTHR10224:SF18; F-BOX DOMAIN-CONTAINING PROTEIN; 1.
DR Pfam; PF12937; F-box-like; 1.
DR SMART; SM00256; FBOX; 1.
DR SUPFAM; SSF81383; F-box domain; 1.
DR SUPFAM; SSF52047; RNI-like; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Biological rhythms; Cytoplasm; Leucine-rich repeat;
KW Nucleus; Reference proteome; Repeat; Ubl conjugation pathway.
FT CHAIN 1..428
FT /note="F-box/LRR-repeat protein 3"
FT /id="PRO_0000119843"
FT DOMAIN 34..81
FT /note="F-box"
FT REPEAT 119..146
FT /note="LRR 1"
FT REPEAT 181..207
FT /note="LRR 2"
FT REPEAT 208..233
FT /note="LRR 3"
FT REPEAT 234..259
FT /note="LRR 4"
FT REPEAT 316..341
FT /note="LRR 5"
FT REPEAT 343..368
FT /note="LRR 6"
FT REPEAT 369..394
FT /note="LRR 7"
FT REGION 1..33
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..29
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 70..117
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_008414"
FT MUTAGEN 22..25
FT /note="KRPR->AAAA: Induces relocalization to the cytosol."
FT /evidence="ECO:0000269|PubMed:23452856"
FT MUTAGEN 143
FT /note="G->E: No effect."
FT /evidence="ECO:0000269|PubMed:23452855"
FT MUTAGEN 358
FT /note="C->S: In after-hour (afh) mutant; lengthening in
FT circadian periodicity."
FT /evidence="ECO:0000269|PubMed:17463252"
FT MUTAGEN 364
FT /note="I->T: In overtime (ovtm) mutant; loss of function,
FT lengthening of the circadian periodiocity and Cry1
FT stabilization of protein levels."
FT /evidence="ECO:0000269|PubMed:17462724"
FT CONFLICT 388
FT /note="S -> F (in Ref. 1; AAF09131)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 428 AA; 48682 MW; 73F2105C89F7F311 CRC64;
MKRGGRDSDQ DSAEEGTAEK PKRPRTTQER SQPCDWGNLL QDIVLHVFKY LPLLDRAHAS
QVCRNWNQVF HMPDLWRCFE FELNQPATSY LKATHPELIK QIIKRHSNHL QYVSFKVDSS
KESAEAACDI LSQLVNCSLK TLGLISTARP SFMDLPKSHF ISALTVVFVN SKSLSSLKID
DTPVDDPSLK VLVANNSDTL KLLKMSSCPH VSPAGILCVA DQCHGLRELA LNYHLLSDEL
LLALSSEKHV RLEHLRIDVV SENPGQTHFH TIQKSSWDAF IKHSPKVNLV MYFFLYEEEF
DPFFRYEIPA THLYFGRSVS KDVLGRVGMT CPRLVELVVC ANGLRPLDEE LIRIAERCKN
LSAIGLGECE VSCSAFVEFV KMCGGRLSQL SIMEEVLIPD QKYSLEQIHW EVSKHLGRVW
FPDMMPTW
//
