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Journal of Neuroscience, Vol 9, 2020-2032, Copyright © 1989 by Society for Neuroscience
Distinct autophosphorylation sites sequentially produce autonomy and inhibition of the multifunctional Ca2+/calmodulin-dependent protein kinase
LL Lou and H Schulman
Department of Pharmacology, Stanford University School of Medicine, California 94305.
The multifunctional Ca2+/calmodulin-dependent protein kinase
(multifunctional CaM kinase) may be an important mediator for
neurotransmitters and hormones that utilize Ca2+ as a "second messenger."
We examined the ability of autophosphorylation to convert the
multifunctional CaM kinase to a Ca2+/calmodulin-independent (autonomous)
form to determine whether autophosphorylation is a mechanism for short- or
long-term enhancement of Ca2+ action. As the kinase incorporates phosphate
during continuous stimulation by Ca2+/calmodulin, its ability to
phosphorylate exogenous substrates becomes increasingly autonomous.
Withdrawal of Ca2+ after a critical level of phosphate incorporation is
reached leads to a "burst" or rapid increase in Ca2+-independent
autophosphorylation. The "burst" of autophosphorylation is distinct from
the initial Ca2+-dependent autophosphorylation, however, since it inhibits
substrate phosphorylation. Both Ca2+-dependent and Ca2+-independent
substrate phosphorylation are inhibited by this autonomous
autophosphorylation. Thus, autophosphorylation has a dual role in
modulating the activity of multifunctional CaM kinase. It initially enables
the kinase to continue phosphorylating substrates after Ca2+ levels
decline, but it eventually suppresses this autonomous activity. Tryptic
phosphopeptide mapping demonstrates that appearance of
phosphothreonine-containing peptides is common to several conditions used
to generate an autonomous enzyme. Sequencing reveals the critical
"autonomy" site to be threonine286. The inhibitory mode of
autophosphorylation involves 3 additional phosphopeptides containing a
serine and a threonine residue.
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