FBXL3

Last updated
FBXL3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FBXL3 , FBL3, FBL3A, FBXL3A, F-box and leucine-rich repeat protein 3, F-box and leucine rich repeat protein 3, IDDSFAS
External IDs OMIM: 605653 MGI: 1354702 HomoloGene: 8127 GeneCards: FBXL3
Orthologs
SpeciesHumanMouse
Entrez

26224

50789

Ensembl

ENSG00000005812

ENSMUSG00000022124

UniProt

Q9UKT7

Q8C4V4

RefSeq (mRNA)

NM_012158

NM_015822
NM_001347600
NM_001347601
NM_001360341
NM_001360342

Contents

RefSeq (protein)

NP_036290

NP_001334529
NP_001334530
NP_056637
NP_001347270
NP_001347271

Location (UCSC) Chr 13: 76.99 – 77.03 Mb Chr 14: 103.32 – 103.34 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3). [5] [6] FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex. [7]

The FBXL3 protein participates in the negative feedback loop responsible for generating molecular circadian rhythms in mammals by binding to the CRY1 and CRY2 proteins to facilitate their polyubiquitination by the SCF complex and their subsequent degradation by the proteasome. [8] [9] [10]

Discovery

The Fbxl3 gene function was independently identified in 2007 by three groups, led by Michele Pagano, Joseph S. Takahashi, Dr. Patrick Nolan and Michael Hastings, respectively. Takahashi used forward genetics N-ethyl-N-nitrosourea (ENU) mutagenesis to screen for mice with varied circadian activity which led to the discovery of the Overtime (Ovtm) mutant of the Fbxl3 gene. [9] Nolan discovered the Fbxl3 mutation After hours (Afh) by a forward screen assessing wheel activity behavior of mutagenized mice. [10] The phenotypes identified in mice were mechanistically explained by Pagano who discovered that the FBXL3 protein is necessary for the reactivation of the CLOCK and BMAL1 protein heterodimer by inducing the degradation of CRY proteins. [8]

Overtime

Mice with the homozygous mutation of Ovtm, free run with an intrinsic period of 26 hours. Overtime is a loss of function mutation caused by a substitution of isoleucine to threonine in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins PER1 and PER2 are decreased, while levels of CRY proteins do not differ from those of wild type mice. The stabilization of CRY protein levels leads to continued repression of Per1 and Per2 transcription and translation. [9]

After-hours

The After-hours mutation is a substitution of cysteine to serine at position 358. Similar to Overtime, the mutation occurs in the region where FBXL3 binds to CRY. Mice homozygous for the Afh mutation have a free running period of about 27 hours. The Afh mutation delays the rate of CRY protein degradation, therefore affecting the transcription of PER2 protein. [8] [10]

Fbxl21

The closest homologue to Fbxl3 is Fbxl21 as it also binds to the CRY1 and CRY2 proteins. Predominantly localized to the cytosol, Fbxl21 has been proposed to antagonize the action of Fbxl3 through ubiquitination and stabilization of CRY proteins instead of leading it to degradation. [11] FBXL21 is expressed predominantly in the suprachiasmatic nucleus, which is the region in the brain that functions as the master pacemaker in mammals. [12]

Characteristics

The human FBXL3 gene is located on the long arm of chromosome 13 at position 22.3. [11] [13] The protein is composed of 428 amino acids and has a mass of 48,707 daltons. [14] The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem leucine-rich repeats used for substrate recognition. It has eight post-translational modification sites involving ubiquitination and four sites involving phosphorylation. The FBXL3 protein is predominantly localized to the nucleus. It is one of four subunits of a ubiquitin ligase complex called SKP1-CUL1-F-box-protein, which includes the proteins CUL1, SKP1, and RBX1. [13] [15]

Function

The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the proteasome. [8] FBXL3 binds to CRY2 by occupying its flavin adenine dinucleotide (FAD) cofactor pocket with a C-terminal tail and buries the PER-binding interface on the CRY2 protein. [16]

The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the Bmal1 gene. Bmal1 expression is regulated by the binding of REV-ERBα and RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the Bmal1 promoter region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression. [17] FBXL3 decreases the repression of Bmal1 transcription by inactivating the REV-ERBα and HDAC3 repressor complex. [18]

The FBXL3 protein has also been found to cooperatively degrade c-MYC when bound to CRY2. The c-MYC protein is a transcription factor important in regulating cell proliferation. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with phosphorylated c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein. [19]

Interactions

FBXL3 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">RAR-related orphan receptor alpha</span> Protein-coding gene in the species Homo sapiens

RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">FBXW7</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

Steve A. Kay is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. and is currently a professor at the University of Southern California. He also served on the Life Sciences jury for the Infosys Prize in 2011.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Carla Beth Green is an American neurobiologist and chronobiologist. She is a professor in the Department of Neuroscience and a Distinguished Scholar in Neuroscience at the University of Texas Southwestern Medical Center. She is the former president of the Society for Research on Biological Rhythms (SRBR), as well as a satellite member of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan.

Carrie L. Partch is an American protein biochemist and circadian biologist. Partch is currently a Professor in the Department of Chemistry and Biochemistry at the University of California, Santa Cruz. She is noted for her work using biochemical and biophysical techniques to study the mechanisms of circadian rhythmicity across multiple organisms. Partch applies principles of chemistry and physics to further her research in the field of biological clocks.

Jet or Jetlag is a gene discovered in Drosophila and other insects. They are a part of the SCF family of ubiquitin ligases that plays a huge role in the circadian pathway by controlling the degradation of TIM, a circadian regulatory protein. The gene plays an important role in resetting the circadian clock by transmitting light from CRY to TIM. Jetlag mutants have been found to impede re-entrainment due to significantly reduced ability to degrade TIM. The F-box protein of the FBXL family named FBXL15 is JET's mammalian homolog.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000005812 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022124 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ GRCh38: Ensembl release 89: ENSG00000005812 - Ensembl, May 2017
  6. ↑ GRCm38: Ensembl release 89: ENSMUSG00000022124 - Ensembl, May 2017
  7. ↑ "Human PubMed Reference:".
  8. 1 2 3 4 Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M (May 2007). "SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins". Science. 316 (5826): 900–4. Bibcode:2007Sci...316..900B. doi:10.1126/science.1141194. PMID   17463251. S2CID   7667826.
  9. 1 2 3 Siepka SM, Yoo SH, Park J, Lee C, Takahashi JS (2007). "Genetics and neurobiology of circadian clocks in mammals". Cold Spring Harbor Symposia on Quantitative Biology. 72: 251–259. doi:10.1101/sqb.2007.72.052. PMC   3749845 . PMID   18419282.
  10. 1 2 3 Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O'neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM (May 2007). "The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period". Science. 316 (5826): 897–900. Bibcode:2007Sci...316..897G. doi:10.1126/science.1141138. PMID   17463252. S2CID   24403152.
  11. 1 2 Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka-Hata H, Nakagawa T, Lanjakornsiripan D, Nakayama KI, Fukada Y (February 2013). "FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes". Cell. 152 (5): 1106–18. doi: 10.1016/j.cell.2013.01.054 . PMID   23452856.
  12. ↑ Dardente H, Mendoza J, Fustin JM, Challet E, Hazlerigg DG (2008). "Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals". PLOS ONE. 3 (10): e3530. Bibcode:2008PLoSO...3.3530D. doi: 10.1371/journal.pone.0003530 . PMC   2568807 . PMID   18953409.
  13. 1 2 3 Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (October 1999). "Identification of a family of human F-box proteins". Current Biology. 9 (20): 1177–9. doi: 10.1016/S0960-9822(00)80020-2 . PMID   10531035.
  14. ↑ Sato K, Yoshida K (November 2010). "Augmentation of the ubiquitin-mediated proteolytic system by F-box and additional motif-containing proteins (Review)". International Journal of Oncology. 37 (5): 1071–6. doi: 10.3892/ijo_00000758 . PMID   20878054.
  15. ↑ "FBXL3 F-box and leucine rich repeat protein 3 [ Homo sapiens (human) ]". Entrez Gene. Retrieved 27 April 2017.
  16. ↑ Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N (April 2013). "SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket". Nature. 496 (7443): 64–8. Bibcode:2013Natur.496...64X. doi:10.1038/nature11964. PMC   3618506 . PMID   23503662.
  17. 1 2 Ko CH, Takahashi JS (October 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 Spec No 2 (Review Issue 2): R271-7. doi: 10.1093/hmg/ddl207 . PMC   3762864 . PMID   16987893.
  18. 1 2 3 Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, Wang X, Gao X, Huang M, Yan J, Yang L, Liu Y, Ptácek LJ, Xu Y (March 2013). "Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock". Proceedings of the National Academy of Sciences of the United States of America. 110 (12): 4750–5. Bibcode:2013PNAS..110.4750S. doi: 10.1073/pnas.1302560110 . PMC   3606995 . PMID   23471982.
  19. 1 2 3 Huber AL, Papp SJ, Chan AB, Henriksson E, Jordan SD, Kriebs A, Nguyen M, Wallace M, Li Z, Metallo CM, Lamia KA (November 2016). "CRY2 and FBXL3 Cooperatively Degrade c-MYC". Molecular Cell. 64 (4): 774–789. doi:10.1016/j.molcel.2016.10.012. PMC   5123859 . PMID   27840026.
  20. ↑ Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N (April 2013). "SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket". Nature. 496 (7443): 64–8. Bibcode:2013Natur.496...64X. doi:10.1038/nature11964. PMC   3618506 . PMID   23503662.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.