Nocturnin

Last updated
NOCT
Human Nocturnin (6MAL).png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NOCT , CCR4L, Ccr4c, NOC, CCRN4L, nocturnin
External IDs OMIM: 608468; MGI: 109382; HomoloGene: 7661; GeneCards: NOCT; OMA:NOCT - orthologs
Orthologs
SpeciesHumanMouse
Entrez

25819

12457

Ensembl

ENSG00000151014

ENSMUSG00000023087

UniProt

Q9UK39

O35710

RefSeq (mRNA)

NM_012118

NM_009834

RefSeq (protein)

NP_036250

NP_033964

Location (UCSC) Chr 4: 139.02 – 139.05 Mb Chr 3: 51.13 – 51.16 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Nocturnin is a human hydrolase enzyme that is involved in metabolism and its expression is controlled by the rhythmic circadian clock. It is encoded by the NOCT gene located on chromosome 4. Nocturnin contains a C-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. A study in January 2019, demonstrated that NADP+ and NADPH are the direct targets of Nocturnin. [5] [6]

Contents

The Drosophila melanogaster ortholog of Nocturnin is Curled. Knockouts of Curled lead to the curled wing phenotype in fruit flies. The curled wing phenotype was first discovered by Thomas Hunt Morgan in 1915. [7] In mice the Nocturnin ortholog is responsible for controlling diet and weight-gain, knockout mice do not gain weight when placed on a high-fat diet, when compared to normal mice containing Nocturnin. [8] In mice it has also been shown that Nocturnin is rhythmically expressed even when mice are placed in complete darkness, demonstrating that Nocturnin expression is driven by our body's internal clock. [9]

Cellular localization

Nocturnin was shown to have a Mitochondrial targeting sequence, which is located on the N-terminus of the protein. [5] [6] The targeting sequence of Nocturnin is cleaved off at the mitochondria to allow entry.

Enzymatic activity

Nocturnin was previously thought to deadenylate mRNAs of metabolic genes, [10] but two studies in 2018 found that Nocturnin does not directly possess ribonuclease activity. [11] [12] A study in January 2019 demonstrated that human Nocturnin is a phosphatase that acts directly on NADP(H) to remove the 2' phosphate. [5] [6] Curled, the Drosophila ortholog, was also shown to be an NADP(H) 2' phosphatase, which indicates that the enzymatic activity is conserved from humans to fruit flies. [5] [6]

Structure

Nocturnin contains a C-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family (EEP). Its protein fold is similar to that of DNase I, AP endonuclease, INPP5B, Sphingomyelin phosphodiesterase, TDP2, PDE12, and CNOT6L. As in the other EEP members, five conserved catalytic residues help coordinate a Magnesium atom, for Nocturnin the divalent metal participates in the NADP(H) phosphatase activity. The first structures of human Nocturnin were solved in 2017-2018 (6BT1, [12] 6BT2, [12] and 6MAL [11] ). All three were of the C-terminal EEP-like domain of Nocturnin bound to its cofactor magnesium. In December 2018, the first structure of Nocturnin bound to its natural substrate, NADPH, was determined, 6NF0. [5] [6]

Related Research Articles

<span class="mw-page-title-main">Dicer</span> Enzyme that cleaves double-stranded RNA (dsRNA) into short dsRNA fragments

Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the DICER1 gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20–25 base pairs long with a two-base overhang on the 3′-end. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide phosphate</span> Chemical compound

Nicotinamide adenine dinucleotide phosphate, abbreviated NADP+ or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADPH as a reducing agent ('hydrogen source'). NADPH is the reduced form, whereas NADP+ is the oxidized form. NADP+ is used by all forms of cellular life.

<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.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

<span class="mw-page-title-main">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<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">Flap structure-specific endonuclease 1</span> Protein-coding gene in the species Homo sapiens

Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.

<span class="mw-page-title-main">Endonuclease/Exonuclease/phosphatase family</span>

Endonuclease/Exonuclease/phosphatase family is a structural domain found in the large family of proteins including magnesium dependent endonucleases and many phosphatases involved in intracellular signaling.

<span class="mw-page-title-main">SBF1</span> Protein-coding gene in the species Homo sapiens

Myotubularin-related protein 5 is a protein that in humans is encoded by the SBF1 gene.

<span class="mw-page-title-main">CNOT6</span> Protein-coding gene in the species Homo sapiens

CCR4-NOT transcription complex subunit 6 is a protein that in humans is encoded by the CNOT6 gene.

<span class="mw-page-title-main">BHLHE41</span> Protein-coding gene in humans

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

<span class="mw-page-title-main">DUSP12</span> Protein-coding gene in the species Homo sapiens

Dual specificity protein phosphatase 12 is an enzyme that in humans is encoded by the DUSP12 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.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

<span class="mw-page-title-main">Endonuclease/exonuclease/phosphatase family domain containing 1</span> Protein-coding gene in the species Homo sapiens

Endonuclease/exonuclease/phosphatase family domain containing 1 is a protein that in humans is encoded by the EEPD1 gene.

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000151014 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000023087 – 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. 1 2 3 4 5 Estrella MA, Du J, Chen L, Rath S, Prangley E, Chitrakar A, Aoki T, Schedl P, Rabinowitz J, Korennykh A (2019). "The Metabolites NADP+ and NADPH are the Targets of the Circadian Protein Nocturnin (Curled)". bioRxiv . 10 (1): 2367. doi: 10.1101/534560 . PMC   6542800 . PMID   31147539.
  6. 1 2 3 4 5 Estrella MA, Du J, Chen L, Rath S, Prangley E, Chitrakar A, Aoki T, Schedl P, Rabinowitz J, Korennykh A (May 2019). "The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled)". Nature Communications . 10 (1): 2367. Bibcode:2019NatCo..10.2367E. doi:10.1038/s41467-019-10125-z. PMC   6542800 . PMID   31147539.
  7. ↑ Gronke S, Bickmeyer I, Wunderlich R, Jackle H, Kuhnlein RP (2009). "curled Encodes the Drosophila Homolog of the Vertebrate Circadian Deadenylase Nocturnin". Genetics . 183 (1): 219–232. doi:10.1534/genetics.109.105601. PMC   2746146 . PMID   19581445.
  8. ↑ Green CB, Douris N, Kojima S, Strayer CA, Fogerty J, Lourim D, Keller SR, Besharse JC (2007). "Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity". PNAS . 104 (23): 9, 888–93. doi: 10.1073/pnas.0702448104 . PMC   1871564 . PMID   17517647.
  9. ↑ Wang Y, Osterbur DL, Megaw PL, Tosini G, Fukuhara C, Green CB, Besharse JC (2001). "Rhythmic expression of Nocturnin mRNA in multiple tissues of the mouse". BMC Developmental Biology . 1 (9): 9. doi: 10.1186/1471-213X-1-9 . PMC   32249 . PMID   11394964.
  10. ↑ Baggs JE, Green CB (2003). "Nocturnin, a Deadenylase in Xenopus laevis Retina". Current Biology . 13 (3): 189–198. doi: 10.1016/S0960-9822(03)00014-9 . PMID   12573214. S2CID   16337386.
  11. 1 2 Estrella MA, Du J, Korennykh A (2018). "Crystal Structure of Human Nocturnin Catalytic Domain". Scientific Reports . 8 (1): 16294. Bibcode:2018NatSR...816294E. doi:10.1038/s41598-018-34615-0. PMC   6214945 . PMID   30389976.
  12. 1 2 3 Abshire ET, Chasseur J, Bohn JA, Del Rizzo PA, Freddolino PL, Goldstrohm AC, Trievel RC (2018). "The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells". Nucleic Acids Research . 46 (12): 6257–6270. doi:10.1093/nar/gky412. PMC   6158716 . PMID   29860338.
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.