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Amino Acids

, Volume 46, Issue 10, pp 2295–2304 | Cite as

The many structural faces of calmodulin: a multitasking molecular jackknife

  • Petri KursulaEmail author
Minireview Article

Abstract

Calmodulin (CaM) is a highly conserved protein and a crucial calcium sensor in eukaryotes. CaM is a regulator of hundreds of diverse target proteins. A wealth of studies has been carried out on the structure of CaM, both in the unliganded form and in complexes with target proteins and peptides. The outcome of these studies points toward a high propensity to attain various conformational states, depending on the binding partner. The purpose of this review is to provide examples of different conformations of CaM trapped in the crystal state. In addition, comparisons are made to corresponding studies in solution. The different CaM conformations in crystal structures are also compared based on the positions of the metal ions bound to their EF hands, in terms of distances, angles, and pseudo-torsion angles. Possible caveats and artifacts in CaM crystal structures are discussed, as well as the possibilities of trapping biologically relevant CaM conformations in the crystal state.

Keywords

Protein conformation Crystal structure Complex Calcium X-Ray crystallography Calmodulin 

Abbreviations

CaM

Calmodulin

CaMK

CaM-dependent kinase

DAPK

Death-associated protein kinase

PDB

Protein Data Bank

Notes

Acknowledgments

This work has been supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, and the Hamburg Foundation for Science and Research.

Conflict of interest

The author declares that he has no conflict of interest.

References

  1. Aoyagi M, Arvai AS, Tainer JA, Getzoff ED (2003) Structural basis for endothelial nitric oxide synthase binding to calmodulin. EMBO J 22:766–775PubMedCrossRefPubMedCentralGoogle Scholar
  2. Ataman ZA, Gakhar L, Sorensen BR, Hell JW, Shea MA (2007) The NMDA receptor NR1 C1 region bound to calmodulin: structural insights into functional differences between homologous domains. Structure 15:1603–1617PubMedCrossRefPubMedCentralGoogle Scholar
  3. Baber JL, Szabo A, Tjandra N (2001) Analysis of slow interdomain motion of macromolecules using NMR relaxation data. J Am Chem Soc 123:3953–3959PubMedCrossRefGoogle Scholar
  4. Babu YS, Bugg CE, Cook WJ (1988) Structure of calmodulin refined at 2.2 A resolution. J Mol Biol 204:191–204PubMedCrossRefGoogle Scholar
  5. Barbato G, Ikura M, Kay LE, Pastor RW, Bax A (1992) Backbone dynamics of calmodulin studied by 15 N relaxation using inverse detected two-dimensional NMR spectroscopy: the central helix is flexible. Biochemistry 31:5269–5278PubMedCrossRefGoogle Scholar
  6. Bertini I, Gelis I, Katsaros N, Luchinat C, Provenzani A (2003) Tuning the affinity for lanthanides of calcium binding proteins. Biochemistry 42:8011–8021PubMedCrossRefGoogle Scholar
  7. Bertini I, Del Bianco C, Gelis I, Katsaros N, Luchinat C, Parigi G, Peana M, Provenzani A, Zoroddu MA (2004) Experimentally exploring the conformational space sampled by domain reorientation in calmodulin. Proc Natl Acad Sci 101:6841–6846PubMedCrossRefPubMedCentralGoogle Scholar
  8. Bertini I, Kursula P, Luchinat C, Parigi G, Vahokoski J, Wilmanns M, Yuan J (2009) Accurate solution structures of proteins from X-ray data and a minimal set of NMR data: calmodulin–peptide complexes as examples. J Am Chem Soc 131:5134–5144PubMedCrossRefGoogle Scholar
  9. Bertini I, Giachetti A, Luchinat C, Parigi G, Petoukhov MV, Pierattelli R, Ravera E, Svergun DI (2010) Conformational space of flexible biological macromolecules from average data. J Am Chem Soc 132:13553–13558PubMedCrossRefGoogle Scholar
  10. Black DJ, Persechini A (2011) In calmodulin–IQ domain complexes, the Ca(2+)-free and Ca(2+)-bound forms of the calmodulin C-lobe direct the N-lobe to different binding sites. Biochemistry 50:10061–10068PubMedCrossRefGoogle Scholar
  11. de Diego I, Kuper J, Bakalova N, Kursula P, Wilmanns M (2010) Molecular basis of the death-associated protein kinase–calcium/calmodulin regulator complex. Sci Signal 3:ra6PubMedCrossRefGoogle Scholar
  12. Drum CL, Yan SZ, Bard J, Shen YQ, Lu D, Soelaiman S, Grabarek Z, Bohm A, Tang WJ (2002) Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin. Nature 415:396–402PubMedCrossRefGoogle Scholar
  13. Fallon JL, Quiocho FA (2003) A closed compact structure of native Ca(2+)-calmodulin. Structure 11:1303–1307PubMedCrossRefGoogle Scholar
  14. Fallon JL, Halling DB, Hamilton SL, Quiocho FA (2005) Structure of calmodulin bound to the hydrophobic IQ domain of the cardiac Ca(v)1.2 calcium channel. Structure 13:1881–1886PubMedCrossRefGoogle Scholar
  15. Fallon JL, Baker MR, Xiong L, Loy RE, Yang G, Dirksen RT, Hamilton SL, Quiocho FA (2009) Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+* calmodulins. Proc Natl Acad Sci 106:5135–5140PubMedCrossRefPubMedCentralGoogle Scholar
  16. Habermann E, Crowell K, Janicki P (1983) Lead and other metals can substitute for Ca2+ in calmodulin. Arch Toxicol 54:61–70PubMedCrossRefGoogle Scholar
  17. Heidorn DB, Seeger PA, Rokop SE, Blumenthal DK, Means AR, Crespi H, Trewhella J (1989) Changes in the structure of calmodulin induced by a peptide based on the calmodulin-binding domain of myosin light chain kinase. Biochemistry 28:6757–6764PubMedCrossRefGoogle Scholar
  18. Heller WT (2005) Influence of multiple well defined conformations on small-angle scattering of proteins in solution. Acta Crystallogr D Biol Crystallogr 61:33–44PubMedCrossRefGoogle Scholar
  19. Houdusse A, Gaucher JF, Krementsova E, Mui S, Trybus KM, Cohen C (2006) Crystal structure of apo-calmodulin bound to the first two IQ motifs of myosin V reveals essential recognition features. Proc Natl Acad Sci 103:19326–19331PubMedCrossRefPubMedCentralGoogle Scholar
  20. Ikura M, Spera S, Barbato G, Kay LE, Krinks M, Bax A (1991) Secondary structure and side-chain 1H and 13C resonance assignments of calmodulin in solution by heteronuclear multidimensional NMR spectroscopy. Biochemistry 30:9216–9228PubMedCrossRefGoogle Scholar
  21. Ikura M, Clore GM, Gronenborn AM, Zhu G, Klee CB, Bax A (1992) Solution structure of a calmodulin–target peptide complex by multidimensional NMR. Science 256:632–638PubMedCrossRefGoogle Scholar
  22. Kranz JK, Lee EK, Nairn AC, Wand AJ (2002) A direct test of the reductionist approach to structural studies of calmodulin activity: relevance of peptide models of target proteins. J Biol Chem 277:16351–16354PubMedCrossRefGoogle Scholar
  23. Krueger JK, Olah GA, Rokop SE, Zhi G, Stull JT, Trewhella J (1997) Structures of calmodulin and a functional myosin light chain kinase in the activated complex: a neutron scattering study. Biochemistry 36:6017–6023PubMedCrossRefGoogle Scholar
  24. Krueger JK, Gallagher SC, Zhi G, Geguchadze R, Persechini A, Stull JT, Trewhella J (2001) Activation of myosin light chain kinase requires translocation of bound calmodulin. J Biol Chem 276:4535–4538PubMedCrossRefGoogle Scholar
  25. Kuczera K, Kursula P (2012) Interactions of calmodulin with death-associated protein kinase peptides: experimental and modeling studies. J Biomol Struct Dyn 30:45–61PubMedCrossRefGoogle Scholar
  26. Kumar V, Chichili VP, Tang X, Sivaraman J (2013a) A novel trans conformation of ligand-free calmodulin. PLoS One 8:e54834PubMedCrossRefPubMedCentralGoogle Scholar
  27. Kumar V, Chichili VP, Zhong L, Tang X, Velazquez-Campoy A, Sheu FS, Seetharaman J, Gerges NZ, Sivaraman J (2013b) Structural basis for the interaction of unstructured neuron specific substrates neuromodulin and neurogranin with calmodulin. Sci Rep 3:1392PubMedPubMedCentralGoogle Scholar
  28. Kurokawa H, Osawa M, Kurihara H, Katayama N, Tokumitsu H, Swindells MB, Kainosho M, Ikura M (2001) Target-induced conformational adaptation of calmodulin revealed by the crystal structure of a complex with nematode Ca(2+)/calmodulin-dependent kinase kinase peptide. J Mol Biol 312:59–68PubMedCrossRefGoogle Scholar
  29. Kursula P (2014) Crystallographic snapshots of initial steps in the collapse of the calmodulin central helix. Acta Crystallogr D Biol Crystallogr 70:24–30PubMedCrossRefGoogle Scholar
  30. Kursula P, Majava V (2007) A structural insight into lead neurotoxicity and calmodulin activation by heavy metals. Acta Crystallogr, Sect F: Struct Biol Cryst Commun 63:653–656CrossRefGoogle Scholar
  31. Majava V, Kursula P (2009) Domain swapping and different oligomeric states for the complex between calmodulin and the calmodulin-binding domain of calcineurin A. PLoS One 4:e5402PubMedCrossRefPubMedCentralGoogle Scholar
  32. Majava V, Petoukhov MV, Hayashi N, Pirila P, Svergun DI, Kursula P (2008) Interaction between the C-terminal region of human myelin basic protein and calmodulin: analysis of complex formation and solution structure. BMC Struct Biol 8:10PubMedCrossRefPubMedCentralGoogle Scholar
  33. Majava V, Wang C, Myllykoski M, Kangas SM, Kang SU, Hayashi N, Baumgartel P, Heape AM, Lubec G, Kursula P (2010) Structural analysis of the complex between calmodulin and full-length myelin basic protein, an intrinsically disordered molecule. Amino Acids 39:59–71PubMedCrossRefGoogle Scholar
  34. Matsubara M, Nakatsu T, Kato H, Taniguchi H (2004) Crystal structure of a myristoylated CAP-23/NAP-22N-terminal domain complexed with Ca2+/calmodulin. EMBO J 23:712–718PubMedCrossRefPubMedCentralGoogle Scholar
  35. Maximciuc AA, Putkey JA, Shamoo Y, Mackenzie KR (2006) Complex of calmodulin with a ryanodine receptor target reveals a novel, flexible binding mode. Structure 14:1547–1556PubMedCrossRefGoogle Scholar
  36. Meador WE, Means AR, Quiocho FA (1992) Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin–peptide complex. Science 257:1251–1255PubMedCrossRefGoogle Scholar
  37. Mori MX, Vander Kooi CW, Leahy DJ, Yue DT (2008) Crystal structure of the CaV2 IQ domain in complex with Ca2+/calmodulin: high-resolution mechanistic implications for channel regulation by Ca2+. Structure 16:607–620PubMedCrossRefPubMedCentralGoogle Scholar
  38. Munnich S, Taft MH, Manstein DJ (2014) Crystal structure of human myosin 1c–the motor in GLUT4 exocytosis: implications for Ca2+ regulation and 14–3–3 binding. J Mol Biol 426:2070–2081PubMedCrossRefGoogle Scholar
  39. Nagulapalli M, Parigi G, Yuan J, Gsponer J, Deraos G, Bamm VV, Harauz G, Matsoukas J, de Planque MR, Gerothanassis IP, Babu MM, Luchinat C, Tzakos AG (2012) Recognition pliability is coupled to structural heterogeneity: a calmodulin intrinsically disordered binding region complex. Structure 20:522–533PubMedCrossRefGoogle Scholar
  40. Osawa M, Tokumitsu H, Swindells MB, Kurihara H, Orita M, Shibanuma T, Furuya T, Ikura M (1999) A novel target recognition revealed by calmodulin in complex with Ca2+-calmodulin-dependent kinase kinase. Nat Struct Biol 6:819–824PubMedCrossRefGoogle Scholar
  41. Patel AK, Yadav RP, Majava V, Kursula I, Kursula P (2011) Structure of the dimeric autoinhibited conformation of DAPK2, a pro-apoptotic protein kinase. J Mol Biol 409:369–383PubMedCrossRefGoogle Scholar
  42. Reddy Chichili VP, Xiao Y, Seetharaman J, Cummins TR, Sivaraman J (2013) Structural basis for the modulation of the neuronal voltage-gated sodium channel NaV1.6 by calmodulin. Sci Rep 3:2435PubMedGoogle Scholar
  43. Reichow SL, Clemens DM, Freites JA, Nemeth-Cahalan KL, Heyden M, Tobias DJ, Hall JE, Gonen T (2013) Allosteric mechanism of water-channel gating by Ca2+-calmodulin. Nat Struct Mol Biol 20:1085–1092PubMedCrossRefPubMedCentralGoogle Scholar
  44. Rellos P, Pike AC, Niesen FH, Salah E, Lee WH, von Delft F, Knapp S (2010) Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation. PLoS Biol 8:e1000426PubMedCrossRefPubMedCentralGoogle Scholar
  45. Rhoads AR, Friedberg F (1997) Sequence motifs for calmodulin recognition. FASEB J 11:331–340PubMedGoogle Scholar
  46. Rumi-Masante J, Rusinga FI, Lester TE, Dunlap TB, Williams TD, Dunker AK, Weis DD, Creamer TP (2012) Structural basis for activation of calcineurin by calmodulin. J Mol Biol 415:307–317PubMedCrossRefPubMedCentralGoogle Scholar
  47. Sarhan MF, Tung CC, Van Petegem F, Ahern CA (2012) Crystallographic basis for calcium regulation of sodium channels. Proc Natl Acad Sci 109:3558–3563PubMedCrossRefPubMedCentralGoogle Scholar
  48. Schumacher MA, Rivard AF, Bachinger HP, Adelman JP (2001) Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 410:1120–1124PubMedCrossRefGoogle Scholar
  49. Schumacher MA, Crum M, Miller MC (2004) Crystal structures of apocalmodulin and an apocalmodulin/SK potassium channel gating domain complex. Structure 12:849–860PubMedCrossRefGoogle Scholar
  50. Shuman H, Greenberg MJ, Zwolak A, Lin T, Sindelar CV, Dominguez R, Ostap EM (2014) A vertebrate myosin-I structure reveals unique insights into myosin mechanochemical tuning. Proc Natl Acad Sci 111:2116–2121PubMedCrossRefPubMedCentralGoogle Scholar
  51. Spera S, Ikura M, Bax A (1991) Measurement of the exchange rates of rapidly exchanging amide protons: application to the study of calmodulin and its complex with a myosin light chain kinase fragment. J Biomol NMR 1:155–165PubMedCrossRefGoogle Scholar
  52. Tidow H, Poulsen LR, Andreeva A, Knudsen M, Hein KL, Wiuf C, Palmgren MG, Nissen P (2012) A bimodular mechanism of calcium control in eukaryotes. Nature 491:468–472PubMedCrossRefGoogle Scholar
  53. Trewhella J, Blumenthal DK, Rokop SE, Seeger PA (1990) Small-angle scattering studies show distinct conformations of calmodulin in its complexes with two peptides based on the regulatory domain of the catalytic subunit of phosphorylase kinase. Biochemistry 29:9316–9324PubMedCrossRefGoogle Scholar
  54. van der Spoel D, de Groot BL, Hayward S, Berendsen HJ, Vogel HJ (1996) Bending of the calmodulin central helix: a theoretical study. Protein Sci 5:2044–2053PubMedCrossRefPubMedCentralGoogle Scholar
  55. Van Petegem F, Chatelain FC, Minor DLJ (2005) Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain-Ca2+/calmodulin complex. Nat Struct Mol Biol 12:1108–1115PubMedCrossRefPubMedCentralGoogle Scholar
  56. Villarroel A, Taglialatela M, Bernardo-Seisdedos G, Alaimo A, Agirre J, Alberdi A, Gomis-Perez C, Soldovieri MV, Ambrosino P, Malo C, Areso P (2014) The ever changing moods of calmodulin: How structural plasticity entails transductional adaptability. J Mol Biol (in press)Google Scholar
  57. Wang C, Chung BC, Yan H, Lee SY, Pitt GS (2012) Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin. Structure 20:1167–1176PubMedCrossRefPubMedCentralGoogle Scholar
  58. Wilson MA, Brunger AT (2000) The 1.0 A crystal structure of Ca(2+)-bound calmodulin: an analysis of disorder and implications for functionally relevant plasticity. J Mol Biol 301:1237–1256PubMedCrossRefGoogle Scholar
  59. Yamada Y, Matsuo T, Iwamoto H, Yagi N (2012) A compact intermediate state of calmodulin in the process of target binding. Biochemistry 51:3963–3970PubMedCrossRefGoogle Scholar
  60. Yang C, Jas GS, Kuczera K (2001) Structure and dynamics of calcium-activated calmodulin in solution. J Biomol Struct Dyn 19:247–271PubMedCrossRefGoogle Scholar
  61. Ye Q, Li X, Wong A, Wei Q, Jia Z (2006) Structure of calmodulin bound to a calcineurin peptide: a new way of making an old binding mode. Biochemistry 45:738–745PubMedCrossRefGoogle Scholar
  62. Ye Q, Wang H, Zheng J, Wei Q, Jia Z (2008) The complex structure of calmodulin bound to a calcineurin peptide. Proteins 73:19–27PubMedCrossRefGoogle Scholar
  63. Ye Q, Feng Y, Yin Y, Faucher F, Currie MA, Rahman MN, Jin J, Li S, Wei Q, Jia Z (2013) Structural basis of calcineurin activation by calmodulin. Cell Signal 25:2661–2667PubMedCrossRefGoogle Scholar
  64. Zhang M, Tanaka T, Ikura M (1995) Calcium-induced conformational transition revealed by the solution structure of apo calmodulin. Nat Struct Biol 2:758–767PubMedCrossRefGoogle Scholar
  65. Zhang M, Abrams C, Wang L, Gizzi A, He L, Lin R, Chen Y, Loll PJ, Pascal JM, Zhang JF (2012) Structural basis for calmodulin as a dynamic calcium sensor. Structure 20:911–923PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  1. 1.Faculty of Biochemistry and Molecular Medicine & Biocenter OuluUniversity of OuluOuluFinland
  2. 2.Department of ChemistryUniversity of HamburgHamburgGermany

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