Myotonic Dystrophy Protein Kinase Domains Mediate Localization, Oligomerization, Novel Catalytic Activity, and Autoinhibition

Human myotonic dystrophy protein kinase (DMPK) is a member of a novel class of multidomain protein kinases that regulate cell size and shape in a variety of organisms. However, little is currently known about the general properties of DMPK including domain function, substrate specificity, and potent...

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Veröffentlicht in:Biochemistry (Easton) 2000-07, Vol.39 (29), p.8480-8490
Hauptverfasser: Bush, Erik W, Helmke, Steve M, Birnbaum, Richard A, Perryman, M. Benjamin
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container_issue 29
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creator Bush, Erik W
Helmke, Steve M
Birnbaum, Richard A
Perryman, M. Benjamin
description Human myotonic dystrophy protein kinase (DMPK) is a member of a novel class of multidomain protein kinases that regulate cell size and shape in a variety of organisms. However, little is currently known about the general properties of DMPK including domain function, substrate specificity, and potential mechanisms of regulation. Two forms of the kinase are expressed in muscle, DMPK-1 and DMPK-2. We demonstrate that the larger DMPK-1 form (the primary translation product) is proteolytically cleaved near the carboxy terminus to generate the smaller DMPK-2 form. We further demonstrate that the coiled-coil domain is required for DMPK oligomerization; coiled-coil mediated oligomerization also correlated with enhanced catalytic activity. DMPK was found to exhibit a novel catalytic activity similar to, but distinct from, related protein kinases such as protein kinase C and A, and the Rho kinases. We observed that recombinant DMPK-1 exhibits low activity, whereas the activity of carboxy-terminally truncated DMPK is increased approximately 3-fold. The inhibitory activity of the full-length kinase was mapped to what appears to be a pseudosubstrate autoinhibitory domain at the extreme carboxy terminus of DMPK. To date, endogenous activators of DMPK are unknown; however, we observed that DMPK purified from cells exposed to the G protein activator GTP-γ-S exhibited an approximately 2-fold increase in activity. These results suggest a general model of DMPK regulation with two main regulatory branches:  short-term activation of the kinase in response to G protein second messengers and long-term activation as a result of proteolysis.
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subjects Amino Acid Sequence
Base Sequence
DNA Primers - genetics
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
In Vitro Techniques
Models, Molecular
Molecular Sequence Data
Myotonic Dystrophy - enzymology
Myotonic Dystrophy - genetics
Myotonin-Protein Kinase
Peptides - chemistry
Peptides - pharmacology
Protein Structure, Quaternary
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
title Myotonic Dystrophy Protein Kinase Domains Mediate Localization, Oligomerization, Novel Catalytic Activity, and Autoinhibition
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