Role of a pineal cAMP-operated arylalkylamine
            <i>N-</i>
            acetyltransferase/14-3-3-binding switch in melatonin synthesis

Ganguly, Shantanu; Gastel, Jonathan A.; Weller, Joan L.; Schwartz, Christian; Jaffe, Howard; Namboodiri, M. A. A.; Coon, Steven L.; Hickman, A.B.; Rollag, Mark D.; Obšil, Tomáš; Beauverger, Philippe; Ferry, Gilles; Boutin, Jean A.; Klein, David C.

doi:10.1073/pnas.141118798

Cited by 181 publications

(227 citation statements)

References 22 publications

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“…Previously, the available evidence indicated only that light-evoked physiological changes in AANAT activity in retina and pineal were attributable to protein degradation (Gastel et al, 1998;Schomerus et al, 2000;Zatz et al, 2000;Falcon et al, 2001;Iuvone et al, 2002). A physiological effect of 14-3-3 binding on the K m of AANAT for amine substrates was inferred based on studies using expressed protiens Ganguly et al, 2001Ganguly et al, , 2005. The current results provide new insight on a mechanism whereby light can rapidly downregulate melatonin synthesis.…”

Section: Discussionmentioning

confidence: 72%

Photic Regulation of ArylalkylamineN-Acetyltransferase Binding to 14-3-3 Proteins in Retinal Photoreceptor Cells

Pozdeyev¹,

Taylor²,

Haque³

et al. 2006

J. Neurosci.

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14-3-3 proteins are a ubiquitous, highly conserved family of chaperone proteins involved in signal transduction, regulation of cell cycle, intracellular trafficking/targeting, cytoskeletal structure, and transcription. Although 14-3-3 proteins are among the most abundant proteins in the CNS, very little is known about their functional roles in the vertebrate retina. In the present study, we demonstrated that photoreceptors express 14-3-3 protein(s) and identified a 14-3-3 binding partner in photoreceptor cells, the melatonin-synthesizing enzyme arylalkylamine N-acetyltransferase (AANAT). Importantly, our data demonstrate that the binding of 14-3-3 to AANAT is regulated by light, with dramatic functional consequences. During the night in darkness, retinal AANAT is phosphorylated and forms a complex with 14-3-3 proteins with an apparent molecular weight of ϳ90 kDa. Phosphorylation of AANAT facilitates the binding of enzyme to 14-3-3 proteins. Within the complex, AANAT is catalytically activated and protected from dephosphorylation and degradation. Light disrupts the AANAT/14-3-3 complex, leading to catalytic inactivation, dephosphorylation, and proteolytic degradation of the enzyme. In the presence of the proteasome inhibitor, lactacystin, light results in the formation of a high molecular weight complex (Ͼ150 kDa), which may represent an intermediate in the AANAT degradation process. These findings provide new insight into the roles of 14-3-3 proteins in photoreceptor cells and to the mechanisms controlling melatonin synthesis in the vertebrate retina.

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Section: Discussionmentioning

confidence: 72%

Photic Regulation of ArylalkylamineN-Acetyltransferase Binding to 14-3-3 Proteins in Retinal Photoreceptor Cells

Pozdeyev¹,

Taylor²,

Haque³

et al. 2006

J. Neurosci.

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“…The pulldown of CAT with 19c⌬T is reminiscent of the copurification of 14-3-3 proteins with serotonin N-acetyltransferase. 14-3-3 protein interacts with serotonin N-acetyltransferase in a phosphorylation dependent manner (47,48). Interestingly, our results showed that recombinant CAT was purified as a phosphorylated protein and readily formed a complex with 19c⌬T and its functionally active mutant 19cFHA in vitro.…”

Section: Discussionmentioning

confidence: 72%

Forkhead-associated Domain-containing Protein Rv0019c and Polyketide-associated Protein PapA5, from Substrates of Serine/Threonine Protein Kinase PknB to Interacting Proteins of Mycobacterium tuberculosis

Gupta

Sajid

Arora

et al. 2009

Journal of Biological Chemistry

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Mycobacterium tuberculosis profoundly exploits protein phosphorylation events carried out by serine/threonine protein kinases (STPKs) for its survival and pathogenicity. Forkheadassociated domains (FHA), the phosphorylation-responsive modules, have emerged as prominent players in STPK mediated signaling. In this study, we demonstrate the association of the previously uncharacterized FHA domain-containing protein Rv0019c with cognate STPK PknB. The consequent phosphorylation of Rv0019c is shown to be dependent on the conserved residues in the Rv0019c FHA domain and activation loop of PknB. Furthermore, by creating deletion mutants we identify Thr 36 as the primary phosphorylation site in Rv0019c. During purification of Rv0019c from Escherichia coli, the E. coli protein chloramphenicol acetyltransferase (CAT) specifically and reproducibly copurifies with Rv0019c in a FHA domain-dependent manner. On the basis of structural similarity of E. coli CAT with M. tuberculosis PapA5, a protein involved in phthiocerol dimycocerosate biosynthesis, PapA5 is identified as an interaction partner of Rv0019c. The interaction studies on PapA5, purified as an unphosphorylated protein from E. coli, with Rv0019c deletion mutants reveal that the residues N-terminal to the functional FHA domain of Rv0019c are critical for formation of the Rv0019c-PapA5 complex and thus constitute a previously unidentified phosphoindependent binding motif. Finally, PapA5 is shown to be phosphorylated on threonine residue(s) by PknB, whereas serine/threonine phosphatase Mstp completely reverses the phosphorylation. Thus, our data provides initial clues for a possible regulation of PapA5 and hence the phthiocerol dimycocerosate biosynthesis by PknB, either by direct phosphorylation of PapA5 or indirectly through Rv0019c.

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“…2). Phosphorylation of these sites promotes binding to 14-3-3 proteins, which reduces the Km for the arylalkylamine substrates and also protects the enzyme from proteasomal proteolysis (Ganguly et al, 2001a;Obsil et al, 2001;Ganguly et al, 2005). In addition, a highly conserved lysine in the N-terminal region, may mediate proteasomal proteolysis Klein et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Evolution of arylalkylamine N-acetyltransferase: Emergence and divergence

Coon

Klein

2006

Molecular and Cellular Endocrinology

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106

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The melatonin rhythm-generating enzyme, arylalkylamine N-acetyltransferase (AANAT) is known to have recognizable ancient homologs in bacteria and fungi, but not in other eukaryotes. Analysis of new cDNA and genomic sequences has identified several additional homologs in other groupings. First, an AANAT homolog has been found in the genome of the cephalochordate amphioxus, representing the oldest homolog in chordates. Second, two AANAT homologs have been identified in unicellular green algae. The homologs in amphioxus, unicellular green algae, fungi and bacteria are similarly primitive in that they lack sequences found in vertebrate AANATs that are involved in regulation and that facilitate binding and catalysis. In addition, all these sequences are intronless. These features are consistent with horizontal transfer of the AANAT ancestor from bacteria to green algae, fungi and chordates. Lastly, a third AANAT gene has been found in teleost fish, suggesting that AANAT genes serve multiple functions in addition to melatonin synthesis.

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Role of a pineal cAMP-operated arylalkylamine N- acetyltransferase/14-3-3-binding switch in melatonin synthesis

Cited by 181 publications

References 22 publications

Photic Regulation of ArylalkylamineN-Acetyltransferase Binding to 14-3-3 Proteins in Retinal Photoreceptor Cells

Photic Regulation of ArylalkylamineN-Acetyltransferase Binding to 14-3-3 Proteins in Retinal Photoreceptor Cells

Forkhead-associated Domain-containing Protein Rv0019c and Polyketide-associated Protein PapA5, from Substrates of Serine/Threonine Protein Kinase PknB to Interacting Proteins of Mycobacterium tuberculosis

Evolution of arylalkylamine N-acetyltransferase: Emergence and divergence

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