6nf0 | pdb_00006nf0
Nocturnin with bound NADPH substrate
Structural highlights
Function[NOCT_HUMAN] Circadian deadenylase which plays an important role in post-transcriptional regulation of metabolic genes under circadian control. Degrades poly(A) tails of specific target mRNAs leading to their degradation and suppression of translation. Exerts a rhythmic post-transcriptional control of genes necessary for metabolic functions including nutrient absorption, glucose/insulin sensitivity, lipid metabolism, adipogenesis, inflammation and osteogenesis. Plays an important role in favoring adipogenesis over osteoblastogenesis and acts as a key regulator of the adipogenesis/osteogenesis balance. Promotes adipogenesis by activating PPARG transcriptional activity in a deadenylase-independent manner by facilitating its nuclear translocation. Regulates circadian expression of NOS2 in the liver and negatively regulates the circadian expression of IGF1 in the bone. Critical for proper development of early embryos (By similarity). Publication Abstract from PubMedNocturnin (NOCT) is a rhythmically expressed protein that regulates metabolism under the control of circadian clock. It has been proposed that NOCT deadenylates and regulates metabolic enzyme mRNAs. However, in contrast to other deadenylases, purified NOCT lacks the deadenylase activity. To identify the substrate of NOCT, we conducted a mass spectrometry screen and report that NOCT specifically and directly converts the dinucleotide NADP(+) into NAD(+) and NADPH into NADH. Further, we demonstrate that the Drosophila NOCT ortholog, Curled, has the same enzymatic activity. We obtained the 2.7 A crystal structure of the human NOCT*NADPH complex, which revealed that NOCT recognizes the chemically unique ribose-phosphate backbone of the metabolite, placing the 2'-terminal phosphate productively for removal. We provide evidence for NOCT targeting to mitochondria and propose that NADP(H) regulation, which takes place at least in part in mitochondria, establishes the molecular link between circadian clock and metabolism. The metabolites NADP(+) and NADPH are the targets of the circadian protein Nocturnin (Curled).,Estrella MA, Du J, Chen L, Rath S, Prangley E, Chitrakar A, Aoki T, Schedl P, Rabinowitz J, Korennykh A Nat Commun. 2019 May 30;10(1):2367. doi: 10.1038/s41467-019-10125-z. PMID:31147539[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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