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.
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Abbreviations
- CaM:
-
Calmodulin
- CaMK:
-
CaM-dependent kinase
- DAPK:
-
Death-associated protein kinase
- PDB:
-
Protein Data Bank
References
Aoyagi M, Arvai AS, Tainer JA, Getzoff ED (2003) Structural basis for endothelial nitric oxide synthase binding to calmodulin. EMBO J 22:766–775
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 15:1603–1617
Baber JL, Szabo A, Tjandra N (2001) Analysis of slow interdomain motion of macromolecules using NMR relaxation data. J Am Chem Soc 123:3953–3959
Babu YS, Bugg CE, Cook WJ (1988) Structure of calmodulin refined at 2.2 A resolution. J Mol Biol 204:191–204
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 31:5269–5278
Bertini I, Gelis I, Katsaros N, Luchinat C, Provenzani A (2003) Tuning the affinity for lanthanides of calcium binding proteins. Biochemistry 42:8011–8021
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 101:6841–6846
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 131:5134–5144
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 132:13553–13558
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 50:10061–10068
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:ra6
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 415:396–402
Fallon JL, Quiocho FA (2003) A closed compact structure of native Ca(2+)-calmodulin. Structure 11:1303–1307
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 13:1881–1886
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 106:5135–5140
Habermann E, Crowell K, Janicki P (1983) Lead and other metals can substitute for Ca2+ in calmodulin. Arch Toxicol 54:61–70
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 28:6757–6764
Heller WT (2005) Influence of multiple well defined conformations on small-angle scattering of proteins in solution. Acta Crystallogr D Biol Crystallogr 61:33–44
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 103:19326–19331
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 30:9216–9228
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 256:632–638
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 277:16351–16354
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 36:6017–6023
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 276:4535–4538
Kuczera K, Kursula P (2012) Interactions of calmodulin with death-associated protein kinase peptides: experimental and modeling studies. J Biomol Struct Dyn 30:45–61
Kumar V, Chichili VP, Tang X, Sivaraman J (2013a) A novel trans conformation of ligand-free calmodulin. PLoS One 8:e54834
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 3:1392
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 312:59–68
Kursula P (2014) Crystallographic snapshots of initial steps in the collapse of the calmodulin central helix. Acta Crystallogr D Biol Crystallogr 70:24–30
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 63:653–656
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:e5402
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 8:10
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 39:59–71
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 23:712–718
Maximciuc AA, Putkey JA, Shamoo Y, Mackenzie KR (2006) Complex of calmodulin with a ryanodine receptor target reveals a novel, flexible binding mode. Structure 14:1547–1556
Meador WE, Means AR, Quiocho FA (1992) Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin–peptide complex. Science 257:1251–1255
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 16:607–620
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 426:2070–2081
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 20:522–533
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 6:819–824
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 409:369–383
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 3:2435
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 20:1085–1092
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:e1000426
Rhoads AR, Friedberg F (1997) Sequence motifs for calmodulin recognition. FASEB J 11:331–340
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 415:307–317
Sarhan MF, Tung CC, Van Petegem F, Ahern CA (2012) Crystallographic basis for calcium regulation of sodium channels. Proc Natl Acad Sci 109:3558–3563
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 410:1120–1124
Schumacher MA, Crum M, Miller MC (2004) Crystal structures of apocalmodulin and an apocalmodulin/SK potassium channel gating domain complex. Structure 12:849–860
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 111:2116–2121
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 1:155–165
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 491:468–472
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 29:9316–9324
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 5:2044–2053
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 12:1108–1115
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)
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 20:1167–1176
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 301:1237–1256
Yamada Y, Matsuo T, Iwamoto H, Yagi N (2012) A compact intermediate state of calmodulin in the process of target binding. Biochemistry 51:3963–3970
Yang C, Jas GS, Kuczera K (2001) Structure and dynamics of calcium-activated calmodulin in solution. J Biomol Struct Dyn 19:247–271
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 45:738–745
Ye Q, Wang H, Zheng J, Wei Q, Jia Z (2008) The complex structure of calmodulin bound to a calcineurin peptide. Proteins 73:19–27
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 25:2661–2667
Zhang M, Tanaka T, Ikura M (1995) Calcium-induced conformational transition revealed by the solution structure of apo calmodulin. Nat Struct Biol 2:758–767
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 20:911–923
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.
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Kursula, P. The many structural faces of calmodulin: a multitasking molecular jackknife. Amino Acids 46, 2295–2304 (2014). https://doi.org/10.1007/s00726-014-1795-y
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DOI: https://doi.org/10.1007/s00726-014-1795-y