Death-Associated Protein Kinase Activity Is Regulated by Coupled Calcium/Calmodulin Binding to Two Distinct Sites

Bertrand Simon, Anne Sophie Huart, Koen Temmerman, Juha Vahokoski, Haydyn D T Mertens, Dana Komadina, Jan Erik Hoffmann, Hayretin Yumerefendi, Dmitri I. Svergun, Petri Kursula, Carsten Schultz, Andrew A. McCarthy, Darren J. Hart, Matthias Wilmanns

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)851-861
Number of pages11
JournalStructure
Volume24
Issue number6
DOIs
StatePublished - Jun 7 2016
Externally publishedYes

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Death-Associated Protein Kinases
Calmodulin
Calcium
Phosphotransferases
Catalytic Domain
Dimerization
Protein Binding
Protein Kinases
Binding Sites
Phosphorylation

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Simon, B., Huart, A. S., Temmerman, K., Vahokoski, J., Mertens, H. D. T., Komadina, D., ... Wilmanns, M. (2016). Death-Associated Protein Kinase Activity Is Regulated by Coupled Calcium/Calmodulin Binding to Two Distinct Sites. Structure, 24(6), 851-861. https://doi.org/10.1016/j.str.2016.03.020

Death-Associated Protein Kinase Activity Is Regulated by Coupled Calcium/Calmodulin Binding to Two Distinct Sites. / Simon, Bertrand; Huart, Anne Sophie; Temmerman, Koen; Vahokoski, Juha; Mertens, Haydyn D T; Komadina, Dana; Hoffmann, Jan Erik; Yumerefendi, Hayretin; Svergun, Dmitri I.; Kursula, Petri; Schultz, Carsten; McCarthy, Andrew A.; Hart, Darren J.; Wilmanns, Matthias.

In: Structure, Vol. 24, No. 6, 07.06.2016, p. 851-861.

Research output: Contribution to journalArticle

Simon, B, Huart, AS, Temmerman, K, Vahokoski, J, Mertens, HDT, Komadina, D, Hoffmann, JE, Yumerefendi, H, Svergun, DI, Kursula, P, Schultz, C, McCarthy, AA, Hart, DJ & Wilmanns, M 2016, 'Death-Associated Protein Kinase Activity Is Regulated by Coupled Calcium/Calmodulin Binding to Two Distinct Sites', Structure, vol. 24, no. 6, pp. 851-861. https://doi.org/10.1016/j.str.2016.03.020
Simon, Bertrand ; Huart, Anne Sophie ; Temmerman, Koen ; Vahokoski, Juha ; Mertens, Haydyn D T ; Komadina, Dana ; Hoffmann, Jan Erik ; Yumerefendi, Hayretin ; Svergun, Dmitri I. ; Kursula, Petri ; Schultz, Carsten ; McCarthy, Andrew A. ; Hart, Darren J. ; Wilmanns, Matthias. / Death-Associated Protein Kinase Activity Is Regulated by Coupled Calcium/Calmodulin Binding to Two Distinct Sites. In: Structure. 2016 ; Vol. 24, No. 6. pp. 851-861.
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