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Structure of the dimeric autoinhibited conformation of DAPK2, a pro-apoptotic protein kinase.

Patel AK, Yadav RP, Majava V, Kursula I, Kursula P
J Mol Biol 409 369-83 (2011)
Related entries: 2yaa, 2yab

Cited: 18 times
EuropePMC logo PMID: 21497605

Abstract

The death-associated protein kinase (DAPK) family has been characterized as a group of pro-apoptotic serine/threonine kinases that share specific structural features in their catalytic kinase domain. Two of the DAPK family members, DAPK1 and DAPK2, are calmodulin-dependent protein kinases that are regulated by oligomerization, calmodulin binding, and autophosphorylation. In this study, we have determined the crystal and solution structures of murine DAPK2 in the presence of the autoinhibitory domain, with and without bound nucleotides in the active site. The crystal structure shows dimers of DAPK2 in a conformation that is not permissible for protein substrate binding. Two different conformations were seen in the active site upon the introduction of nucleotide ligands. The monomeric and dimeric forms of DAPK2 were further analyzed for solution structure, and the results indicate that the dimers of DAPK2 are indeed formed through the association of two apposed catalytic domains, as seen in the crystal structure. The structures can be further used to build a model for DAPK2 autophosphorylation and to compare with closely related kinases, of which especially DAPK1 is an actively studied drug target. Our structures also provide a model for both homodimerization and heterodimerization of the catalytic domain between members of the DAPK family. The fingerprint of the DAPK family, the basic loop, plays a central role in the dimerization of the kinase domain.

Reviews - 2ya9 mentioned but not cited (1)

  1. Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores. Gógl G, Kornev AP, Reményi A, Taylor SS. Trends Biochem Sci 44 300-311 (2019)


Reviews citing this publication (7)

  1. The DAPK family: a structure-function analysis. Shiloh R, Bialik S, Kimchi A. Apoptosis 19 286-297 (2014)
  2. Death-associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes. Farag AK, Roh EJ. Med Res Rev 39 349-385 (2019)
  3. The many structural faces of calmodulin: a multitasking molecular jackknife. Kursula P. Amino Acids 46 2295-2304 (2014)
  4. Structural and functional diversity in the activity and regulation of DAPK-related protein kinases. Temmerman K, Simon B, Wilmanns M. FEBS J 280 5533-5550 (2013)
  5. Death-associated protein kinase 2: Regulator of apoptosis, autophagy and inflammation. Geering B. Int J Biochem Cell Biol 65 151-154 (2015)
  6. Biochemical and functional characterization of the ROC domain of DAPK establishes a new paradigm of GTP regulation in ROCO proteins. Bialik S, Kimchi A. Biochem Soc Trans 40 1052-1057 (2012)
  7. Structural insights into the functional roles of 14-3-3 proteins. Obsilova V, Obsil T. Front Mol Biosci 9 1016071 (2022)

Articles citing this publication (10)

  1. Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy. Shiloh R, Gilad Y, Ber Y, Eisenstein M, Aweida D, Bialik S, Cohen S, Kimchi A. Nat Commun 9 1759 (2018)
  2. Death-Associated Protein Kinase Activity Is Regulated by Coupled Calcium/Calmodulin Binding to Two Distinct Sites. Simon B, Huart AS, Temmerman K, Vahokoski J, Mertens HD, Komadina D, Hoffmann JE, Yumerefendi H, Svergun DI, Kursula P, Schultz C, McCarthy AA, Hart DJ, Wilmanns M. Structure 24 851-861 (2016)
  3. Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation. Truebestein L, Hornegger H, Anrather D, Hartl M, Fleming KD, Stariha JTB, Pardon E, Steyaert J, Burke JE, Leonard TA. Proc Natl Acad Sci U S A 118 e2101496118 (2021)
  4. 14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites. Horvath M, Petrvalska O, Herman P, Obsilova V, Obsil T. Commun Biol 4 986 (2021)
  5. Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation. Levina A, Fleming KD, Burke JE, Leonard TA. Nat Commun 13 1874 (2022)
  6. Interactions of calmodulin with death-associated protein kinase peptides: experimental and modeling studies. Kuczera K, Kursula P. J Biomol Struct Dyn 30 45-61 (2012)
  7. PKD autoinhibition in trans regulates activation loop autophosphorylation in cis. Reinhardt R, Hirzel K, Link G, Eisler SA, Hägele T, Parson MAH, Burke JE, Hausser A, Leonard TA. Proc Natl Acad Sci U S A 120 e2212909120 (2023)
  8. A critical evaluation of protein kinase regulation by activation loop autophosphorylation. Reinhardt R, Leonard TA. Elife 12 e88210 (2023)
  9. High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor. Geldenhuys WJ, Bergeron SA, Mullins JE, Aljammal R, Gaasch BL, Chen WC, Yun J, Hazlehurst LA. Bioorg Med Chem Lett 27 2029-2037 (2017)
  10. PK1 from Drosophila obscurin is an inactive pseudokinase with scaffolding properties. Zacharchenko T, Dorendorf T, Locker N, Van Dijk E, Katzemich A, Diederichs K, Bullard B, Mayans O. Open Biol 13 220350 (2023)


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