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dc.contributor.authorJorge Finnigan, Anaen_US
dc.contributor.authorKleppe, Runeen_US
dc.contributor.authorK C, Kunwar Jungen_US
dc.contributor.authorYing, Mingen_US
dc.contributor.authorMarie, Michael Bruno Ericen_US
dc.contributor.authorRios Mondragon, Ivanen_US
dc.contributor.authorSalvatore, Michael Fen_US
dc.contributor.authorSaraste, Jaakkoen_US
dc.contributor.authorMartinez, Auroraen_US
dc.date.accessioned2018-04-09T12:25:09Z
dc.date.available2018-04-09T12:25:09Z
dc.date.issued2017
dc.PublishedJorge Finnigan AJ, Kleppe R, K C KJ, Ying M, Marie MBE, Rios Mondragon I, Salvatore, Saraste J, Martinez A. Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules. Journal of Biological Chemistry. 2017;292(34):14092-14107eng
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttps://hdl.handle.net/1956/17587
dc.description.abstractTyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine into L-DOPA, which is the rate-limiting step in the synthesis of catecholamines, such as dopamine, in dopaminergergic neurons. Low dopamine levels and death of the dopaminergic neurons are hallmarks of Parkinson's disease (PD), where α-synuclein is also a key player. TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail. However, the functional role of TH phosphorylation at the Ser-31 site (THSer(P)-31) remains unclear. Here, we report that THSer(P)-31 co-distributes with the Golgi complex and synaptic-like vesicles in rat and human dopaminergic cells. We also found that the TH microsomal fraction content decreases after inhibition of cyclin-dependent kinase 5 (Cdk5) and ERK1/2. The cellular distribution of an overexpressed phospho-null mutant, TH1-S31A, was restricted to the soma of neuroblastoma cells, with decreased association with the microsomal fraction, whereas a phospho-mimic mutant, TH1-S31E, was distributed throughout the soma and neurites. TH1-S31E associated with vesicular monoamine transporter 2 (VMAT2) and α-synuclein in neuroblastoma cells, and endogenous THSer(P)-31 was detected in VMAT2– and α-synuclein–immunoprecipitated mouse brain samples. Microtubule disruption or co-transfection with α-synuclein A53T, a PD-associated mutation, caused TH1-S31E accumulation in the cell soma. Our results indicate that Ser-31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably toward the projection terminals. These findings disclose a new mechanism of TH regulation by phosphorylation and reveal its interaction with key players in PD, opening up new research avenues for better understanding dopamine synthesis in physiological and pathological states.en_US
dc.language.isoengeng
dc.publisherASBMBeng
dc.titlePhosphorylation at serine 31 targets tyrosine hydroxylase tovesicles for transport along microtubulesen_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2018-01-22T14:10:09Z
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.identifier.doihttps://doi.org/10.1074/jbc.m116.762344
dc.identifier.cristin1541953
dc.source.journalJournal of Biological Chemistry
dc.relation.projectNorges forskningsråd: 210731
dc.relation.projectEU: Marie Curie IF Program Grant PIEF-GA-2011-299972
dc.relation.projectNorges forskningsråd: 214012
dc.identifier.citationJournal of Biological Chemistry. 2017, 292 (34), 14092-14107.


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