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]
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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]
References
- GRCh38: Ensembl release 89: ENSG00000151014 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000023087 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 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.
- 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.
- "Circadian clock and fat metabolism linked through newly discovered mechanism". ScienceDaily (Press release). May 30, 2019.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.