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Impressions from the Conformational and Configurational Space Captured by Protein Kinase CK2

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Book cover Protein Kinase CK2 Cellular Function in Normal and Disease States

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 12))

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Abstract

As key components of cellular regulation and signal transduction, eukaryotic protein kinases (EPKs) are strictly regulated. Sophisticated control mechanisms of EPKs are necessary which typically include conformational changes of the enzymes in critical regions. Local structural plasticity is therefore a prerequisite of normal EPK function. Protein kinase CK2, a member of the CMGC family of EPKs, was regarded as an exception from this rule for a long time due to its constitutive activity (lack of an inactive state) and due to its structural rigidity in typical EPK control regions of its catalytic subunit CK2α like the activation segment and the helix αC. Gradually, however, several cases of inherent local plasticity within CK2α were detected, and questions about their crosstalk and their functional significance became an issue. It is very likely now that structural plasticity and dynamics is more important for CK2 function than believed previously. Novel interpretation methods of crystallographic data even confirm an allosteric communication between the ATP site and CK2β-binding site of CK2α which had been only hypothetically postulated before. Similarly, local mobilities of CK2α are subject to modern computational approaches suggesting conformational equilibria in solution as assumed previously. In summary, CK2 structural biology has reached now a mature phase in which sophisticated modern techniques overcome the limitations of classical crystallography so that structural dynamics rather than single “snapshots” is investigated.

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References

  1. Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282

    Article  CAS  PubMed  Google Scholar 

  2. Taylor SS, Keshwani MM, Steichen JM, Kornev AP (2012) Evolution of the eukaryotic protein kinases as dynamic molecular switches. Philos Trans R Soc Lond B Biol Sci 367:2517–2528

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Taylor SS, Ilouz R, Zhang P, Kornev AP (2012) Assembly of allosteric macromolecular switches: lessons from PKA. Nat Rev Mol Cell Biol 13:646–658

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Taylor SS, Kornev AP (2011) Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 36:65–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Jura N, Zhang X, Endres NF, Seeliger MA, Schindler T, Kuriyan J (2011) Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell 42:9–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Niefind K, Guerra B, Ermakowa I, Issinger O-G (2001) Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme. EMBO J 20:5320–5331

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Niefind K, Guerra B, Pinna LA, Issinger O-G, Schomburg D (1998) Crystal structure of the catalytic subunit of protein kinase CK2 from Zea mays at 2.1 Å resolution. EMBO J 17:2451–2462

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Niefind K, Raaf J, Issinger O-G (2009) Protein kinase CK2: from structures to insights. Cell Mol Life Sci 66:1800–1816

    Article  CAS  PubMed  Google Scholar 

  9. Raaf J, Klopffleisch K, Issinger O-G, Niefind K (2008) The catalytic subunit of human protein kinase CK2 structurally deviates from its maize homologue in complex with the nucleotide competitive inhibitor emodin. J Mol Biol 377:1–8

    Article  CAS  PubMed  Google Scholar 

  10. Raaf J, Issinger O-G, Niefind K (2009) First inactive conformation of CK2α, the catalytic subunit of protein kinase CK2. J Mol Biol 386:1212–1221

    Article  CAS  PubMed  Google Scholar 

  11. Niefind K, Issinger O-G (2010) Conformational plasticity of the catalytic subunit of protein kinase CK2 and its consequences for regulation and drug design. Biochim Biophys Acta 1804:484–492

    Article  CAS  PubMed  Google Scholar 

  12. Battistutta R, Lolli G (2011) Structural and functional determinants of protein kinase CK2α: facts and open questions. Mol Cell Biochem 356:67–73

    Article  CAS  PubMed  Google Scholar 

  13. Bischoff N, Raaf J, Olsen B, Bretner M, Issinger O-G, Niefind K (2011) Enzymatic activity with an incomplete catalytic spine: insights from a comparative structural analysis of human CK2α and its paralogous isoform CK2α’. Mol Cell Biochem 356:57–65

    Article  CAS  PubMed  Google Scholar 

  14. Papinutto E, Ranchio A, Lolli G, Pinna LA, Battistutta R (2012) Structural and functional analysis of the flexible regions of the catalytic alpha-subunit of protein kinase CK2. J Struct Biol 177:382–391

    Article  CAS  PubMed  Google Scholar 

  15. Klopffleisch K, Issinger OG, Niefind K (2012) Low-density crystal packing of human protein kinase CK2 catalytic subunit in complex with resorufin or other ligands: a tool to study the unique hinge-region plasticity of the enzyme without packing bias. Acta Crystallogr D68:883–892

    Google Scholar 

  16. Gouron A, Milet A, Jamet H (2014) Conformational flexibility of human casein kinase catalytic subunit explored by metadynamics. Biophys J 106:1134–1141

    Article  CAS  PubMed  Google Scholar 

  17. Artymiuk PJ, Blake CC, Grace DE, Oatley SJ, Phillips DC, Sternberg MJ (1979) Crystallographic studies of the dynamic properties of lysozyme. Nature 280:563–568

    Article  CAS  PubMed  Google Scholar 

  18. Lang PT, Ng HL, Fraser JS, Corn JE, Echols N, Sales M, Holton JM, Alber T (2010) Automated electron-density sampling reveals widespread conformational polymorphism in proteins. Protein Sci 19:1420–1431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Lang PT, Holton JM, Fraser JS, Alber T (2014) Protein structural ensembles are revealed by redefining X-ray electron density noise. Proc Natl Acad Sci U S A 111:237–242

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Fraser JS, van den Bedem H, Samelson AJ, Lang PT, Holton JM, Echols N, Alber T (2011) Accessing protein conformational ensembles using room-temperature X-ray crystallography. Proc Natl Acad Sci U S A 108:16247–16252

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Thompson EE, Kornev AP, Kannan N, Kim C, Ten Eyck LF, Taylor SS (2009) Comparative surface geometry of the protein kinase family. Protein Sci 18:2016–2026

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Biondi RM, Cheung PC, Casamayor A, Deak M, Currie RA, Alessi DR (2000) Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA. EMBO J 19:979–988

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Sarno S, Ghisellini P, Pinna LA (2002) Unique activation mechanism of protein kinase CK2: the N-terminal segment is essential for constitutive activity of the catalytic subunit but not of the holoenzyme. J Biol Chem 277:22509–22514

    Article  CAS  PubMed  Google Scholar 

  24. Nakaniwa T, Kinoshita T, Sekiguchi Y, Tada T, Nakanishi I, Kitaura K, Suzuki Y, Ohno H, Hirasawa A, Tsujimoto G (2009) Structure of human protein kinase CK2α2 with a potent indazole-derivative inhibitor. Acta Crystallogr F65:75–79

    Google Scholar 

  25. Bischoff N, Olsen B, Raaf J, Bretner M, Issinger O-G, Niefind K (2011) Structure of the human protein kinase CK2 catalytic subunit CK2α’ and interaction thermodynamics with the regulatory subunit CK2β. J Mol Biol 407:1–12

    Article  CAS  PubMed  Google Scholar 

  26. Raaf J, Brunstein E, Issinger O-G, Niefind K (2008) The interaction of CK2α and CK2β, the subunits of protein kinase CK2, requires CK2β in a preformed conformation and is enthalpically driven. Protein Sci 17:2180–2186

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Battistutta R, Sarno S, De Moliner E, Papinutto E, Zanotti G, Pinna LA (2000) The replacement of ATP by the competitive inhibitor emodin induces conformational modifications in the catalytic site of protein kinase CK2. J Biol Chem 275:29618–29622

    Article  CAS  PubMed  Google Scholar 

  28. Ermakova I, Boldyreff B, Issinger O-G, Niefind K (2003) Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit. J Mol Biol 330:925–934

    Article  CAS  PubMed  Google Scholar 

  29. Raaf J, Brunstein E, Issinger OG, Niefind K (2008) The CK2α/CK2β interface of human protein kinase CK2 harbors a binding pocket for small molecules. Chem Biol 15:111–117

    Article  CAS  PubMed  Google Scholar 

  30. Raaf J, Guerra B, Neundorf I, Bopp B, Issinger O-G, Jose J, Pietsch M, Niefind K (2013) First structure of protein kinase CK2 catalytic subunit with an effective CK2β-competitive ligand. ACS Chem Biol 8:901–907

    Article  CAS  PubMed  Google Scholar 

  31. Niefind K, Issinger O-G (2005) Primary and secondary interactions between CK2α and CK2β lead to ring-like structures in the crystals of the CK2 holoenzyme. Mol Cell Biochem 274:3–14

    Article  CAS  PubMed  Google Scholar 

  32. Lolli G, Ranchio A, Battistutta R (2014) Active form of the protein kinase CK2 α2β2 holoenzyme is a strong complex with symmetric architecture. ACS Chem Biol 9:366–371

    Article  CAS  PubMed  Google Scholar 

  33. Schnitzler A, Olsen BB, Issinger O-G, Niefind K (2014) The protein kinase CK2Andante holoenzyme structure supports proposed models of autoregulation and trans-autophosphorylation. J Mol Biol 426:1871–1882

    Article  CAS  PubMed  Google Scholar 

  34. Valero E, De Bonis S, Filhol O, Wade RH, Langowski J, Chambaz EM, Cochet C (1995) Quaternary structure of casein kinase 2. Characterization of multiple oligomeric states and relation with its catalytic activity. J Biol Chem 270:8345–8352

    Article  CAS  PubMed  Google Scholar 

  35. Poole A, Poore T, Bandhakavi S, McCann RO, Hanna DE, Glover CV (2005) A global view of CK2 function and regulation. Mol Cell Biochem 274:163–170

    Article  CAS  PubMed  Google Scholar 

  36. Craveur P, Joseph AP, Poulain P, de Brevern AG, Rebehmed J (2013) Cis-trans isomerization of omega dihedrals in proteins. Amino Acids 45:279–289

    Article  CAS  PubMed  Google Scholar 

  37. Jabs A, Weiss MS, Hilgenfeld R (1999) Non-proline cis peptide bonds in proteins. J Mol Biol 286:291–304

    Article  CAS  PubMed  Google Scholar 

  38. Andreotti AH (2003) Native state proline isomerization: an intrinsic molecular switch. Biochemistry 42:9515–9524

    Article  CAS  PubMed  Google Scholar 

  39. Lu KP, Finn G, Lee TH, Nicholson LK (2007) Prolyl cis-trans isomerization as a molecular timer. Nat Chem Biol 3:619–629

    Article  CAS  PubMed  Google Scholar 

  40. Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM (1991) Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253:407–414

    Article  CAS  PubMed  Google Scholar 

  41. Niefind K, Pütter M, Guerra B, Issinger O-G, Schomburg D (1999) GTP plus water mimic ATP in the active site of protein kinase CK2. Nat Struct Biol 6:1100–1103

    Article  CAS  PubMed  Google Scholar 

  42. Yde CW, Ermakova I, Issinger OG, Niefind K (2005) Inclining the purine base binding plane in protein kinase CK2 by exchanging the flanking side-chains generates a preference for ATP as a cosubstrate. J Mol Biol 347:399–414

    Article  CAS  PubMed  Google Scholar 

  43. Pinna LA (2002) Protein kinase CK2: a challenge to canons. J Cell Sci 115:3873–3878

    Article  CAS  PubMed  Google Scholar 

  44. Traxler P, Furet P (1999) Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther 82:195–206

    Article  CAS  PubMed  Google Scholar 

  45. Miyashita O, Onuchic JN, Wolynes PG (2003) Nonlinear elasticity, proteinquakes, and the energy landscapes of functional transitions in proteins. Proc Natl Acad Sci U S A 100:12570–12575

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Shan Y, Arkhipov A, Kim ET, Pan AC, Shaw DE (2013) Transitions to catalytically inactive conformations in EGFR kinase. Proc Natl Acad Sci U S A 110:7270–7275

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Raaf J, Bischoff N, Klopffleisch K, Brunstein E, Olsen BB, Vilk G, Litchfield DW, Issinger O-G, Niefind K (2011) Interaction between CK2α and CK2β, the subunits of protein kinase CK2: thermodynamic contributions of key residues on the CK2α surface. Biochemistry 50:512–522

    Article  CAS  PubMed  Google Scholar 

  48. Niefind K, Yde CW, Ermakova I, Issinger O-G (2007) Evolved to be active: sulfate ions define substrate recognition sites of CK2alpha and emphasise its exceptional role within the CMGC family of eukaryotic protein kinases. J Mol Biol 370:427–438

    Article  CAS  PubMed  Google Scholar 

  49. Chantalat L, Leroy D, Filhol O, Nueda A, Benitez MJ, Chambaz EM, Cochet C, Dideberg O (1999) Crystal structure of the human protein kinase CK2 regulatory subunit reveals its zinc finger-mediated dimerization. EMBO J 18:2930–2940

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Battistutta R (2009) Protein kinase CK2 in health and disease: structural bases of protein kinase CK2 inhibition. Cell Mol Life Sci 66:1868–1889

    Article  CAS  PubMed  Google Scholar 

  51. Liu H, Wang H, Teng M, Li X (2014) The multiple nucleotide-divalent cation binding modes of Saccharomyces cerevisiae CK2α indicate a possible co-substrate hydrolysis product (ADP/GDP) release pathway. Acta Crystallogr D70:501–513

    Google Scholar 

  52. The PyMOL Molecular Graphics System, Version 1.7, Schrödinger, LLC

    Google Scholar 

  53. Laudet B, Barette C, Dulery V, Renaudet O, Dumy P, Metz A, Prudent R, Deshiere A, Dideberg O, Filhol O, Cochet C (2007) Structure-based design of small peptide inhibitors of protein kinase CK2 subunit interaction. Biochem J 408:363–373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgement

The contributions of Anja Asendorf, Anna Köhler and Nicole Splett are gratefully acknowledged. The work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) to KNI (NI 643/4–1).

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Authors and Affiliations

  1. KinaseDetect ApS, Skovvej 22, DK-6340, Kruså, Denmark

    Jennifer Hochscherf & Olaf-Georg Issinger

  2. Department of Chemistry, Institute of Biochemistry, University of Cologne, Otto-Fischer-Str. 12-14, D-50674, Cologne, Germany

    Alexander Schnitzler & Karsten Niefind

Authors
  1. Jennifer Hochscherf
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  2. Alexander Schnitzler
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  3. Olaf-Georg Issinger
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  4. Karsten Niefind
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Correspondence to Karsten Niefind .

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Editors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School and Minneapolis VA Health Care System, Minneapolis, Minnesota, USA

    Khalil Ahmed

  2. Dept of Biochemistry & Molecular Biology, University of Southern Denmark, Odense, Denmark

    Olaf-Georg Issinger

  3. Department of Molecular Biology, The John Paul II Catholic U. of Lublin Institute of Biotechnology, Lublin, Poland

    Ryszard Szyszka

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Hochscherf, J., Schnitzler, A., Issinger, OG., Niefind, K. (2015). Impressions from the Conformational and Configurational Space Captured by Protein Kinase CK2. In: Ahmed, K., Issinger, OG., Szyszka, R. (eds) Protein Kinase CK2 Cellular Function in Normal and Disease States. Advances in Biochemistry in Health and Disease, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-319-14544-0_2

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