FXL21_MOUSE
ID FXL21_MOUSE Reviewed; 434 AA.
AC Q8BFZ4; B2RSN8; Q8BIJ8; Q8BIW5;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=F-box/LRR-repeat protein 21;
DE AltName: Full=F-box and leucine-rich repeat protein 21;
DE AltName: Full=F-box and leucine-rich repeat protein 3B;
DE AltName: Full=F-box/LRR-repeat protein 3B;
GN Name=Fbxl21; Synonyms=Fbl21, Fbxl3b;
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 [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J; TISSUE=Kidney, Thymus, and Urinary bladder;
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 [2]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP FUNCTION, 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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CRY1 AND CRY2,
RP IDENTIFICATION IN A SCF PROTEIN LIGASE COMPLEX, AND MUTAGENESIS OF GLY-149.
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 [6]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CRY1 AND CRY2,
RP IDENTIFICATION IN A SCF PROTEIN LIGASE COMPLEX, AND DISRUPTION PHENOTYPE.
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).
CC -!- FUNCTION: Substrate-recognition component of the SCF(FBXL21) 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(FBXL21) complex mainly acts in the
CC cytosol and mediates ubiquitination of CRY proteins (CRY1 and CRY2),
CC leading to CRY proteins stabilization. The SCF(FBXL21) complex
CC counteracts the activity of the SCF(FBXL3) complex and protects CRY
CC proteins from degradation. Involved in the hypothalamic suprachiasmatic
CC nucleus (SCN) clock regulating temporal organization of the daily
CC activities. {ECO:0000269|PubMed:18953409, ECO:0000269|PubMed:23452855,
CC ECO:0000269|PubMed:23452856}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase
CC complex SCF(FBXL21) composed of CUL1, SKP1, RBX1 and FBXL21. Interacts
CC with CRY1 and CRY2. {ECO:0000269|PubMed:18953409,
CC ECO:0000269|PubMed:23452855, ECO:0000269|PubMed:23452856}.
CC -!- INTERACTION:
CC Q8BFZ4; P97784: Cry1; NbExp=10; IntAct=EBI-6898235, EBI-1266607;
CC Q8BFZ4; Q9R194: Cry2; NbExp=4; IntAct=EBI-6898235, EBI-1266619;
CC Q8BFZ4; Q13616: CUL1; Xeno; NbExp=3; IntAct=EBI-6898235, EBI-359390;
CC Q8BFZ4; P63208: SKP1; Xeno; NbExp=3; IntAct=EBI-6898235, EBI-307486;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Nucleus. Note=Mainly
CC localizes in the cytosol. Present at low level in the nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BFZ4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BFZ4-2; Sequence=VSP_008415, VSP_008416;
CC -!- TISSUE SPECIFICITY: Expressed in the hypothalamus, especially in the
CC suprachiasmatic nucleus (SCN). Expression is driven by the core-clock.
CC There is a pronounced diurnal and circadian expression rhythms rising
CC rapidly at the start of the day and declining at the onset of the
CC night. {ECO:0000269|PubMed:18953409}.
CC -!- DISRUPTION PHENOTYPE: Mice show normal periodicity of wheel-running
CC rhythms with compromised organization of daily activities: mice do not
CC display significant difference from their wild-type littermates in both
CC the free-running period in constant darkness (DD) and activity onset in
CC 12 hours of light/12 hours of darkness (LD). However, an alteration in
CC the daily activities is observed: while wild-type mice show 2 peaks of
CC activity during the active period, the late night activity is
CC eliminated in Fbxl21-deficient mice. Mice lacking both Fbxl3 and Fbxl21
CC show an attenuated phenotype in behavioral rhythm compared to Fbxl3-
CC deficient mice; however, they exhibit unstable behavioral rhythms,
CC sometimes eliciting arrhythmicity. {ECO:0000269|PubMed:23452856}.
CC -!- CAUTION: The mechanism by which the SCF(FBXL21) complex stabilizes CRY
CC proteins (CRY1 and CRY2) is still unclear: according to a report, the
CC SCF(FBXL21) complex does not catalyze 'Lys-48'-linked polyubiquitin
CC chains, but catalyzes a different type of ubiquitin chains that do not
CC lead to degradation (PubMed:23452856). According to a second report,
CC FBXL21 has a higher affinity for CRY proteins compared to FBXL3, while
CC the SCF(FBXL21) complex has weaker ubiquitin-ligase activity compared
CC to the SCF(FBXL3) complex: as a consequence, the SCF(FBXL21) complex
CC protects CRY proteins from SCF(FBXL3) activity and degradation in the
CC nucleus, while it promotes slow degradation of CRY proteins in the
CC cytosol (PubMed:23452855). {ECO:0000305|PubMed:23452855,
CC ECO:0000305|PubMed:23452856}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC37751.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK035290; BAC29018.1; -; mRNA.
DR EMBL; AK079800; BAC37751.1; ALT_INIT; mRNA.
DR EMBL; AK085598; BAC39482.1; -; mRNA.
DR EMBL; CH466546; EDL41240.1; -; Genomic_DNA.
DR EMBL; BC138940; AAI38941.1; -; mRNA.
DR EMBL; BC138941; AAI38942.1; -; mRNA.
DR CCDS; CCDS26563.1; -. [Q8BFZ4-1]
DR RefSeq; NP_001333661.1; NM_001346732.1.
DR RefSeq; NP_848789.2; NM_178674.4. [Q8BFZ4-1]
DR AlphaFoldDB; Q8BFZ4; -.
DR SMR; Q8BFZ4; -.
DR BioGRID; 229415; 4.
DR IntAct; Q8BFZ4; 7.
DR STRING; 10090.ENSMUSP00000112518; -.
DR iPTMnet; Q8BFZ4; -.
DR PhosphoSitePlus; Q8BFZ4; -.
DR PaxDb; Q8BFZ4; -.
DR PRIDE; Q8BFZ4; -.
DR ProteomicsDB; 271616; -. [Q8BFZ4-1]
DR DNASU; 213311; -.
DR Ensembl; ENSMUST00000045428; ENSMUSP00000035248; ENSMUSG00000035509. [Q8BFZ4-1]
DR GeneID; 213311; -.
DR KEGG; mmu:213311; -.
DR UCSC; uc007qsp.1; mouse. [Q8BFZ4-2]
DR UCSC; uc007qsr.1; mouse. [Q8BFZ4-1]
DR CTD; 213311; -.
DR MGI; MGI:2442921; Fbxl21.
DR VEuPathDB; HostDB:ENSMUSG00000035509; -.
DR eggNOG; KOG1947; Eukaryota.
DR GeneTree; ENSGT00940000159491; -.
DR HOGENOM; CLU_033637_0_0_1; -.
DR InParanoid; Q8BFZ4; -.
DR OMA; HVILRVF; -.
DR OrthoDB; 1027299at2759; -.
DR PhylomeDB; Q8BFZ4; -.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 213311; 5 hits in 73 CRISPR screens.
DR PRO; PR:Q8BFZ4; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q8BFZ4; protein.
DR Bgee; ENSMUSG00000035509; Expressed in cortical plate and 55 other tissues.
DR ExpressionAtlas; Q8BFZ4; baseline and differential.
DR Genevisible; Q8BFZ4; MM.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IMP:UniProtKB.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR036047; F-box-like_dom_sf.
DR InterPro; IPR001810; F-box_dom.
DR InterPro; IPR032675; LRR_dom_sf.
DR Pfam; PF12937; F-box-like; 1.
DR SMART; SM00256; FBOX; 1.
DR SUPFAM; SSF81383; SSF81383; 1.
DR PROSITE; PS50181; FBOX; 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..434
FT /note="F-box/LRR-repeat protein 21"
FT /id="PRO_0000119874"
FT DOMAIN 39..85
FT /note="F-box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00080"
FT REPEAT 187..213
FT /note="LRR 1"
FT REPEAT 214..239
FT /note="LRR 2"
FT REPEAT 242..265
FT /note="LRR 3"
FT REPEAT 322..347
FT /note="LRR 4"
FT REPEAT 349..374
FT /note="LRR 5"
FT REPEAT 375..400
FT /note="LRR 6"
FT VAR_SEQ 124..128
FT /note="DSSTE -> QSSFR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_008415"
FT VAR_SEQ 129..434
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_008416"
FT MUTAGEN 149
FT /note="G->E: In Past-time (Psttm) mutant; causes period
FT shortening due to Cry1 and Cry2 destabilization."
FT /evidence="ECO:0000269|PubMed:23452855"
SQ SEQUENCE 434 AA; 49154 MW; DAE94BEC79D1D4A2 CRC64;
MKRNNFSAVN KVVQSSPVVK QPKRGLCSSL RQTHALSVLL DWGTLPHHVI LQIFQYLPLI
DRARASSVCR RWNEVFHIPD LWRKFEFELN QSATSYFKST HPDLIQQIIK KHAAHLQYVS
FKVDSSTESA EAACDILSQL VNCSIQTLGL ISTAKPSFMN VPKSHFVSAL TVVFVNSKSL
SSIKIEDTPV DDPSLKILVA NNSDTLRLLK MSSCPHVSSD GILCVADHCQ GLRELALNYY
ILSDEILLAL SSETHVNLEH LRIDVVSENP GQIKFHSIKK RSWDALIKHS PRVNVVMYFF
LYEEEFEAFF KEETPVTHLY FGRSVSRAIL GRIGLNCPRL IELVVCANGL LPLDSELIRI
AKHCKNLTSL GLSECEVSCS AFVEFVRLCG RRLTQLSIME EVLVPDDRYT PDEVHTEVSK
HLGRVWFPDV MPIW
