Journal
STRUCTURE
Volume 24, Issue 6, Pages 851-861Publisher
CELL PRESS
DOI: 10.1016/j.str.2016.03.020
Keywords
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Funding
- ESRF [ID14-4]
- DORIS [BW7A, X11]
- AstraZeneca
- EMBL Interdisciplinary Post-doctoral fellowship under Marie Curie Actions (COFUND)
- EC [LSHG-CT-2005-512028]
- DFG [SPP1623]
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The regulation of many protein kinases by binding to calcium/calmodulin connects two principal mechanisms in signaling processes: protein phosphorylation and responses to dose-and time-dependent calcium signals. We used the calcium/calmodulin-dependent members of the death-associated protein kinase (DAPK) family to investigate the role of a basic DAPK signature loop near the kinase active site. In DAPK2, this loop comprises a novel dimerization-regulated calcium/calmodulin-binding site, in addition to a well-established calcium/calmodulin site in the C-terminal autoregulatory domain. Unexpectedly, impairment of the basic loop interaction site completely abolishes calcium/calmodulin binding and DAPK2 activity is reduced to a residual level, indicative of coupled binding to the two sites. This contrasts with the generally accepted view that kinase calcium/calmodulin interactions are autonomous of the kinase catalytic domain. Our data establish an intricate model of multi-step kinase activation and expand our understanding of how calcium binding connects with other mechanisms involved in kinase activity regulation.
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