Nocturnin

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]

NOCT
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 6MAL
Identifiers
Aliases	NOCT, CCR4L, Ccr4c, NOC, CCRN4L, nocturnin
External IDs	OMIM: 608468 MGI: 109382 HomoloGene: 7661 GeneCards: NOCT
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q31.1 Start 139,015,781 bp[1] End 139,045,939 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 C Start 51,224,447 bp[2] End 51,251,644 bp[2]
Gene ontology Molecular function • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • metal ion binding • RNA binding • nuclease activity • exonuclease activity • hydrolase activity • poly(A)-specific ribonuclease activity • mRNA binding • 3'-5'-exoribonuclease activity Cellular component • P-body • nucleoplasm • cytoplasm • perinuclear region of cytoplasm • cell nucleus • CCR4-NOT complex Biological process • regulation of embryonic development • RNA phosphodiester bond hydrolysis, exonucleolytic • rhythmic process • deadenylation-dependent decapping of nuclear-transcribed mRNA • mRNA processing • transcription from RNA polymerase II promoter • cytoplasmic mRNA processing body assembly • response to extracellular stimulus • response to lipopolysaccharide • regulation of transcription, DNA-templated • circadian rhythm • regulation of circadian rhythm • negative regulation of osteoblast differentiation • mRNA stabilization • negative regulation of gene expression • positive regulation of fat cell differentiation • circadian regulation of gene expression • nucleic acid phosphodiester bond hydrolysis • nuclear-transcribed mRNA poly(A) tail shortening Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
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: 51.22 – 51.25 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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]

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 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]

References

1. GRCh38: Ensembl release 89: ENSG00000151014 - Ensembl, May 2017
2. 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. 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. doi:10.1101/534560.
6. 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. doi:10.1038/s41467-019-10125-z. PMC 6542800. PMID 31147539. Lay summary – Science Daily.
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.
11. Estrella MA, Du J, Korennykh A (2018). "Crystal Structure of Human Nocturnin Catalytic Domain". Scientific Reports. 8 (1): 16294. doi:10.1038/s41598-018-34615-0. PMC 6214945. PMID 30389976.
12. 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.

External links

• Overview of all the structural information available in the PDB for UniProt: Q9UK39 (Nocturnin) at the PDBe-KB.