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Protein

F-box/LRR-repeat protein 3

Gene

Fbxl3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation. The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2. Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex.6 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Molecular functioni

GO - Biological processi

  • circadian rhythm Source: Reactome
  • entrainment of circadian clock by photoperiod Source: UniProtKB
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein destabilization Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • regulation of circadian rhythm Source: UniProtKB
  • SCF-dependent proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Biological rhythms, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-MMU-400253. Circadian Clock.
R-MMU-508751. Circadian Clock.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
F-box/LRR-repeat protein 3
Alternative name(s):
F-box and leucine-rich repeat protein 3A
F-box/LRR-repeat protein 3A
Protein after-hours
Protein overtime
Gene namesi
Name:Fbxl3
Synonyms:Afh, Fbl3a, Fbxl3a, Ovtm
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:1354702. Fbxl3.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB
  • SCF ubiquitin ligase complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice show defects in behavioral rhythms with an extremely long-period activity phenotype. The onset of active phase is abnormally delayed from the light-to-dark transition: in constant darkness (DD), mice show significantly longer rhythmic activities. Mice lacking both Fbxl3 and Fbxl21 show an attenuated phenotype in behavioral rhythm compared to Fbxl3-deficient mice; however, they exhibit unstable behavioral rhythms, sometimes eliciting arrhythmicity.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi22 – 254KRPR → AAAA: Induces relocalization to the cytosol. 1 Publication
Mutagenesisi143 – 1431G → E: No effect. 1 Publication
Mutagenesisi358 – 3581C → S in after-hour (afh) mutant; lengthening in circadian periodicity. 1 Publication
Mutagenesisi364 – 3641I → T in overtime (ovtm) mutant; loss of function, lengthening of the circadian periodiocity and Cry1 stabilization of protein levels. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 428428F-box/LRR-repeat protein 3PRO_0000119843Add
BLAST

Proteomic databases

MaxQBiQ8C4V4.
PaxDbiQ8C4V4.
PRIDEiQ8C4V4.

PTM databases

iPTMnetiQ8C4V4.
PhosphoSiteiQ8C4V4.

Expressioni

Tissue specificityi

Ubiquitously expressed but enriched in brain. Diffusely expressed in the suprachiasmatic nucleus, SCN.2 Publications

Gene expression databases

BgeeiQ8C4V4.
CleanExiMM_FBXL3.
ExpressionAtlasiQ8C4V4. baseline and differential.
GenevisibleiQ8C4V4. MM.

Interactioni

Subunit structurei

Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL3) composed of CUL1, SKP1, RBX1 and FBXL3. Interacts with CRY1 and CRY2 (phosphorylated).4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Cry1P9778412EBI-1266589,EBI-1266607
Cry2Q9R1946EBI-1266589,EBI-1266619
CUL1Q136163EBI-1266589,EBI-359390From a different organism.
Per2O549432EBI-1266589,EBI-1266779
SKP1P632083EBI-1266589,EBI-307486From a different organism.

Protein-protein interaction databases

BioGridi206121. 3 interactions.
IntActiQ8C4V4. 7 interactions.
STRINGi10090.ENSMUSP00000022720.

Structurei

3D structure databases

ProteinModelPortaliQ8C4V4.
SMRiQ8C4V4. Positions 35-428.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini34 – 8148F-boxAdd
BLAST
Repeati119 – 14628LRR 1Add
BLAST
Repeati181 – 20727LRR 2Add
BLAST
Repeati208 – 23326LRR 3Add
BLAST
Repeati234 – 25926LRR 4Add
BLAST
Repeati316 – 34126LRR 5Add
BLAST
Repeati343 – 36826LRR 6Add
BLAST
Repeati369 – 39426LRR 7Add
BLAST

Sequence similaritiesi

Contains 1 F-box domain.Curated
Contains 7 LRR (leucine-rich) repeats.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiENOG410KDKT. Eukaryota.
ENOG410XT8H. LUCA.
GeneTreeiENSGT00390000007432.
HOGENOMiHOG000060185.
HOVERGENiHBG051587.
InParanoidiQ8C4V4.
KOiK10269.
OMAiCRSWNQV.
OrthoDBiEOG7HB596.
PhylomeDBiQ8C4V4.
TreeFamiTF352583.

Family and domain databases

Gene3Di3.80.10.10. 1 hit.
InterProiIPR001810. F-box_dom.
IPR032675. L_dom-like.
[Graphical view]
PfamiPF00646. F-box. 1 hit.
[Graphical view]
SMARTiSM00256. FBOX. 1 hit.
[Graphical view]
SUPFAMiSSF81383. SSF81383. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8C4V4-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MKRGGRDSDQ DSAEEGTAEK PKRPRTTQER SQPCDWGNLL QDIVLHVFKY
60 70 80 90 100
LPLLDRAHAS QVCRNWNQVF HMPDLWRCFE FELNQPATSY LKATHPELIK
110 120 130 140 150
QIIKRHSNHL QYVSFKVDSS KESAEAACDI LSQLVNCSLK TLGLISTARP
160 170 180 190 200
SFMDLPKSHF ISALTVVFVN SKSLSSLKID DTPVDDPSLK VLVANNSDTL
210 220 230 240 250
KLLKMSSCPH VSPAGILCVA DQCHGLRELA LNYHLLSDEL LLALSSEKHV
260 270 280 290 300
RLEHLRIDVV SENPGQTHFH TIQKSSWDAF IKHSPKVNLV MYFFLYEEEF
310 320 330 340 350
DPFFRYEIPA THLYFGRSVS KDVLGRVGMT CPRLVELVVC ANGLRPLDEE
360 370 380 390 400
LIRIAERCKN LSAIGLGECE VSCSAFVEFV KMCGGRLSQL SIMEEVLIPD
410 420
QKYSLEQIHW EVSKHLGRVW FPDMMPTW
Length:428
Mass (Da):48,682
Last modified:March 1, 2003 - v1
Checksum:i73F2105C89F7F311
GO
Isoform 2 (identifier: Q8C4V4-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     70-117: Missing.

Show »
Length:380
Mass (Da):42,857
Checksum:i20ED3AF140F4B756
GO

Sequence cautioni

The sequence AAF09131.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAH46330.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAM92567.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti388 – 3881S → F in AAF09131 (PubMed:10531037).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei70 – 11748Missing in isoform 2. 1 PublicationVSP_008414Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF176521 mRNA. Translation: AAF09131.1. Different initiation.
AK080863 mRNA. Translation: BAC38050.1.
AE013600 Genomic DNA. Translation: AAM92567.1. Different initiation.
BC046330 mRNA. Translation: AAH46330.1. Different initiation.
CCDSiCCDS27315.1. [Q8C4V4-1]
RefSeqiNP_056637.1. NM_015822.2. [Q8C4V4-1]
XP_006519302.1. XM_006519239.2. [Q8C4V4-1]
XP_006519303.1. XM_006519240.2. [Q8C4V4-2]
XP_006519304.1. XM_006519241.2. [Q8C4V4-1]
XP_006519305.1. XM_006519242.2. [Q8C4V4-2]
UniGeneiMm.214746.

Genome annotation databases

EnsembliENSMUST00000022720; ENSMUSP00000022720; ENSMUSG00000022124. [Q8C4V4-1]
ENSMUST00000132004; ENSMUSP00000115843; ENSMUSG00000022124. [Q8C4V4-2]
ENSMUST00000145693; ENSMUSP00000116044; ENSMUSG00000022124. [Q8C4V4-1]
GeneIDi50789.
KEGGimmu:50789.
UCSCiuc007uwh.1. mouse. [Q8C4V4-2]
uc007uwi.1. mouse. [Q8C4V4-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF176521 mRNA. Translation: AAF09131.1. Different initiation.
AK080863 mRNA. Translation: BAC38050.1.
AE013600 Genomic DNA. Translation: AAM92567.1. Different initiation.
BC046330 mRNA. Translation: AAH46330.1. Different initiation.
CCDSiCCDS27315.1. [Q8C4V4-1]
RefSeqiNP_056637.1. NM_015822.2. [Q8C4V4-1]
XP_006519302.1. XM_006519239.2. [Q8C4V4-1]
XP_006519303.1. XM_006519240.2. [Q8C4V4-2]
XP_006519304.1. XM_006519241.2. [Q8C4V4-1]
XP_006519305.1. XM_006519242.2. [Q8C4V4-2]
UniGeneiMm.214746.

3D structure databases

ProteinModelPortaliQ8C4V4.
SMRiQ8C4V4. Positions 35-428.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi206121. 3 interactions.
IntActiQ8C4V4. 7 interactions.
STRINGi10090.ENSMUSP00000022720.

PTM databases

iPTMnetiQ8C4V4.
PhosphoSiteiQ8C4V4.

Proteomic databases

MaxQBiQ8C4V4.
PaxDbiQ8C4V4.
PRIDEiQ8C4V4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000022720; ENSMUSP00000022720; ENSMUSG00000022124. [Q8C4V4-1]
ENSMUST00000132004; ENSMUSP00000115843; ENSMUSG00000022124. [Q8C4V4-2]
ENSMUST00000145693; ENSMUSP00000116044; ENSMUSG00000022124. [Q8C4V4-1]
GeneIDi50789.
KEGGimmu:50789.
UCSCiuc007uwh.1. mouse. [Q8C4V4-2]
uc007uwi.1. mouse. [Q8C4V4-1]

Organism-specific databases

CTDi26224.
MGIiMGI:1354702. Fbxl3.

Phylogenomic databases

eggNOGiENOG410KDKT. Eukaryota.
ENOG410XT8H. LUCA.
GeneTreeiENSGT00390000007432.
HOGENOMiHOG000060185.
HOVERGENiHBG051587.
InParanoidiQ8C4V4.
KOiK10269.
OMAiCRSWNQV.
OrthoDBiEOG7HB596.
PhylomeDBiQ8C4V4.
TreeFamiTF352583.

Enzyme and pathway databases

UniPathwayiUPA00143.
ReactomeiR-MMU-400253. Circadian Clock.
R-MMU-508751. Circadian Clock.

Miscellaneous databases

ChiTaRSiFbxl3. mouse.
PROiQ8C4V4.
SOURCEiSearch...

Gene expression databases

BgeeiQ8C4V4.
CleanExiMM_FBXL3.
ExpressionAtlasiQ8C4V4. baseline and differential.
GenevisibleiQ8C4V4. MM.

Family and domain databases

Gene3Di3.80.10.10. 1 hit.
InterProiIPR001810. F-box_dom.
IPR032675. L_dom-like.
[Graphical view]
PfamiPF00646. F-box. 1 hit.
[Graphical view]
SMARTiSM00256. FBOX. 1 hit.
[Graphical view]
SUPFAMiSSF81383. SSF81383. 1 hit.
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  2. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Strain: C57BL/6J.
    Tissue: Adrenal gland.
  3. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
    Strain: FVB/N-3.
    Tissue: Mammary tumor.
  5. "Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression."
    Siepka S.M., Yoo S.H., Park J., Song W., Kumar V., Hu Y., Lee C., Takahashi J.S.
    Cell 129:1011-1023(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CIRCADIAN CLOCK, TISSUE SPECIFICITY, INTERACTION WITH CRY1 AND CRY2, MUTAGENESIS OF ILE-364.
  6. Cited for: FUNCTION IN CIRCADIAN CLOCK, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-358.
  7. "Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals."
    Dardente H., Mendoza J., Fustin J.M., Challet E., Hazlerigg D.G.
    PLoS ONE 3:E3530-E3530(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CIRCADIAN CLOCK, INTERACTION WITH CRY1, TISSUE SPECIFICITY.
  8. "Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm."
    Yoo S.H., Mohawk J.A., Siepka S.M., Shan Y., Huh S.K., Hong H.K., Kornblum I., Kumar V., Koike N., Xu M., Nussbaum J., Liu X., Chen Z., Chen Z.J., Green C.B., Takahashi J.S.
    Cell 152:1091-1105(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CIRCADIAN CLOCK, SUBCELLULAR LOCATION, INTERACTION WITH CRY1 AND CRY2, IDENTIFICATION IN A SCF PROTEIN LIGASE COMPLEX, MUTAGENESIS OF GLY-143.
  9. "FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes."
    Hirano A., Yumimoto K., Tsunematsu R., Matsumoto M., Oyama M., Kozuka-Hata H., Nakagawa T., Lanjakornsiripan D., Nakayama K.I., Fukada Y.
    Cell 152:1106-1118(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CIRCADIAN CLOCK, SUBCELLULAR LOCATION, INTERACTION WITH CRY1 AND CRY2, IDENTIFICATION IN A SCF PROTEIN LIGASE COMPLEX, DISRUPTION PHENOTYPE, MUTAGENESIS OF 22-LYS--ARG-25.
  10. "Distinct and separable roles for endogenous CRY1 and CRY2 within the circadian molecular clockwork of the suprachiasmatic nucleus, as revealed by the Fbxl3(Afh) mutation."
    Anand S.N., Maywood E.S., Chesham J.E., Joynson G., Banks G.T., Hastings M.H., Nolan P.M.
    J. Neurosci. 33:7145-7153(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CIRCADIAN CLOCK.

Entry informationi

Entry nameiFBXL3_MOUSE
AccessioniPrimary (citable) accession number: Q8C4V4
Secondary accession number(s): Q80V32, Q8K1W0, Q9QXW1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 3, 2003
Last sequence update: March 1, 2003
Last modified: June 8, 2016
This is version 112 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.