Protein kinase C isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity.

The Journal of Biological Chemistry
Tomas DobranskyR Jane Rylett

Abstract

Choline acetyltransferase (ChAT) synthesizes acetylcholine in cholinergic neurons; regulation of its activity or response to physiological stimuli is poorly understood. We show that ChAT is differentially phosphorylated by protein kinase C (PKC) isoforms on four serines (Ser-440, Ser-346, Ser-347, and Ser-476) and one threonine (Thr-255). This phosphorylation is hierarchical, with phosphorylation at Ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. Ser-476 with Ser-440 and Ser-346/347 maintains basal ChAT activity. Ser-440 is targeted by Arg-442 for phosphorylation by PKC. Arg-442 is mutated spontaneously (R442H) in congenital myasthenic syndrome, rendering ChAT inactive and causing neuromuscular failure. This mutation eliminates phosphorylation of Ser-440, and Arg-442, not phosphorylation of Ser-440, appears primarily responsible for ChAT activity, with Ser-440 phosphorylation modulating catalysis. Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity.

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Citations

Sep 2, 2005·Journal of Neurochemistry·Tomas Dobransky, R Jane Rylett
Oct 16, 2008·Journal of Neuroscience Research·Alison BurgessIsabelle Aubert
Feb 22, 2005·Protein Expression and Purification·Ae-Ri KimBrian H Shilton
Jul 31, 2012·Biotechnology Advances·Jeong-Hun KangYoshiki Katayama
Oct 1, 2013·Behavioural Brain Research·Lin LiGert Lubec
Nov 10, 2009·Archiv der Pharmazie·Miao-Kun Sun, Daniel L Alkon
Apr 18, 2017·Journal of the American Chemical Society·Jeremy W MasonWilliam R Roush
Dec 6, 2006·Biochemistry·Ae-Ri KimBrian H Shilton

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