Abstract
Calmodulin (CaM) is a highly conserved eukaryotic Ca2+ sensor protein that is able to bind a large variety of target sequences without a defined consensus sequence. The recognition of this diverse target set allows CaM to take part in the regulation of several vital cell functions. To fully understand the structural basis of the regulation functions of CaM, the investigation of complexes of CaM and its targets is essential. In this minireview we give an outline of the different types of CaM - peptide complexes with 3D structure determined, also providing an overview of recently determined structures. We discuss factors defining the orientations of peptides within the complexes, as well as roles of anchoring residues. The emphasis is on complexes where multiple binding modes were found.
Keywords: Calcium, calmodulin, EF-hands, calmodulin-peptide complexes, protein-peptide interaction, binding motifs.
Graphical Abstract
[1]
Collins, J.H.; Greaser, M.L.; Potter, J.D.; Horn, M.J. Determination of the amino acid sequence of troponin C from rabbit skeletal muscle. J. Biol. Chem., 1977, 252(18), 6356-6362.
[2]
Barbato, G.; Ikura, M.; Kay, L.E.; Pastor, R.W.; Bax, A. Backbone dynamics of calmodulin studied by 15N relaxation using inverse detected two-dimensional NMR spectroscopy: The central helix is flexible. Biochemistry, 1992, 31(23), 5269-5278.
[3]
Zhang, M.; Tanaka, T.; Ikura, M. Calcium-induced conformational transition revealed by the solution structure of apo-calmodulin. Nat. Struct. Mol. Biol., 1995, 2, 758-767.
[4]
Babu, Y.S.; Bugg, C.E.; Cook, W.J. Structure of calmodulin refined at 2.2 A resolution. J. Mol. Biol., 1988, 204(1), 191-204.
[5]
Walsh, M.P. Calmodulin and the regulation of smooth muscle contraction. Mol. Cell. Biochem., 1994, 135(1), 21-41.
[6]
Rasmussen, C.D.; Means, A.R. Calmodulin, cell growth and gene expression. Trends Neurosci., 1989, 12(11), 433-438.
[7]
Rasmussen, C.D.; Means, A.R. Calmodulin is involved in regulation of cell proliferation. EMBO J., 1987, 6(13), 3961-3968.
[8]
Takuwa, N.; Zhou, W.; Takuwa, Y. Calcium, calmodulin and cell cycle progression. Cell. Signal., 1995, 7(2), 93-104.
[9]
Soderling, T.R. Calcium/calmodulin-dependent protein kinase II: Role in learning and memory. Mol. Cell. Biochem., 1993, 127-128, 93-101.
[10]
Swulius, M.T.; Waxham, M.N. Ca(2+)/calmodulin-dependent protein kinases. Cell. Mol. Life Sci., 2008, 65(17), 2637-2657.
[11]
Chin, D.; Means, A.R. Calmodulin: A prototypical calcium sensor. Trends Cell Biol., 2000, 10(8), 322-328.
[13]
Iacovelli, L.; Sallese, M.; Mariggiò, S.; de Blasi, A. Regulation of G-protein-coupled receptor kinase subtypes by calcium sensor proteins. FASEB J., 1999, 13(1), 1-8.
[14]
Picton, C.; Klee, C.B.; Cohen, P. The regulation of muscle phosphorylase kinase by calcium ions, calmodulin and troponin-C. Cell Calcium, 1981, 2(4), 281-294.
[15]
Roth, S.M.; Schneider, D.M.; Strobel, L.A.; VanBerkum, M.F.; Means, A.R.; Wand, A.J. Structure of the smooth muscle myosin light-chain kinase calmodulin-binding domain peptide bound to calmodulin. Biochemistry, 1991, 30(42), 10078-10084.
[16]
Chin, D.; Winkler, K.E.; Means, A.R. Characterization of substrate phosphorylation and use of calmodulin mutants to address implications from the enzyme crystal structure of calmodulin-dependent protein kinase I. J. Biol. Chem., 1997, 272(50), 31235-31240.
[17]
O’Neil, K.T.; DeGrado, W.F. How calmodulin binds its targets: sequence independent recognition of amphiphilic alpha-helices. Trends Biochem. Sci., 1990, 15(2), 59-64.
[18]
Mayur, Y.C.; Jagadeesh, S.; Thimmaiah, K.N. Targeting calmodulin in reversing multi drug resistance in cancer cells. Mini Rev. Med. Chem., 2006, 6(12), 1383-1389.
[19]
Nyegaard, M.; Overgaard, M.T.; Søndergaard, M.T.; Vranas, M.; Behr, E.R.; Hildebrandt, L.L.; Lund, J.; Hedley, P.L.; Camm, A.J.; Wettrell, G.; Fosdal, I.; Christiansen, M.; Børglum, A.D. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am. J. Hum. Genet., 2012, 91(4), 703-712.
[20]
Søndergaard, M.T.; Liu, Y.; Larsen, K.T.; Nani, A.; Tian, X.; Holt, C.; Wang, R.; Wimmer, R.; Van Petegem, F.; Fill, M.; Chen, S.R.W.; Overgaard, M.T. The arrhythmogenic calmodulin p.Phe142Leu mutation impairs C-domain Ca2+ binding but not calmodulin-dependent inhibition of the cardiac ryanodine receptor. J. Biol. Chem., 2017, 292(4), 1385-1395.
[21]
Pipilas, D.C.; Johnson, C.N.; Webster, G.; Schlaepfer, J.; Fellmann, F.; Sekarski, N.; Wren, L.M.; Ogorodnik, K.V.; Chazin, D.M.; Chazin, W.J.; Crotti, L.; Bhuiyan, Z.A.; George, A.L., Jr Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes. Heart Rhythm, 2016, 13(10), 2012-2019.
[22]
Rhoads, A.R.; Friedberg, F. Sequence motifs for calmodulin recognition. FASEB J., 1997, 11(5), 331-340.
[23]
Tidow, H.; Nissen, P. Structural diversity of calmodulin binding to its target sites. FEBS J., 2013, 280(21), 5551-5565.
[24]
Xu, Q.; Chang, A.; Tolia, A.; Minor, D.L. Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation. J. Mol. Biol., 2013, 425(2), 378-394.
[25]
Houdusse, A.; Gaucher, J.F.; Krementsova, E.; Mui, S.; Trybus, K.M.; Cohen, C. Crystal structure of apo-calmodulin bound to the first two IQ motifs of myosin V reveals essential recognition features. Proc. Natl. Acad. Sci. USA, 2006, 103(51), 19326-19331.
[26]
Li, J.; Chen, Y.; Deng, Y.; Unarta, I.C.; Lu, Q.; Huang, X.; Zhang, M. Ca2+-induced rigidity change of the myosin VIIa IQ motif-single a helix lever arm extension. Structure, 2017, 25(4), 579-591.
[27]
Mori, M.; Konno, T.; Morii, T.; Nagayama, K.; Imoto, K. Regulatory interaction of sodium channel IQ-motif with calmodulin C-terminal lobe. Biochem. Biophys. Res. Commun., 2003, 307(2), 290-296.
[28]
Feldkamp, M.D.; Yu, L.; Shea, M.A. Structural and energetic determinants of Apo calmodulin binding to the IQ motif of the NaV1.2 voltage-dependent sodium channel. Structure, 2011, 19(5), 733-747.
[29]
Chagot, B.; Chazin, W.J. Solution NMR structure of apo-calmodulin in complex with the IQ motif of human cardiac sodium channel NaV1.5. J. Mol. Biol., 2012, 406(1), 106-119.
[30]
Chichili, V.P.R.; Xiao, Y.; Seetharaman, J.; Cummins, T.R.; Sivaraman, J. Structural basis for the modulation of the neuronal voltage-gated sodium channel NaV1.6 by calmodulin. Sci. Rep., 2013, 3, 2435.
[31]
Kumar, V.; Chichili, V.P.R.; Zhong, L.; Tang, X.; Velazquez-Campoy, A.; Sheu, F.S.; Seetharaman, J.; Gerges, N.Z.; Sivaraman, J. Structural basis for the interaction of unstructured neuron specific substrates neuromodulin and neurogranin with calmodulin. Sci. Rep., 2013, 3, 1392.
[32]
Hovey, L.; Fowler, C.A.; Mahling, R.; Lin, Z.; Miller, M.S.; Marx, D.C.; Yoder, J.B.; Kim, E.H.; Tefft, K.M.; Waite, B.C.; Feldkamp, M.D.; Yu, L.; Shea, M.A. Calcium triggers reversal of calmodulin on nested anti-parallel sites in the IQ motif of the neuronal voltage-dependent sodium channel NaV1.2. Biophys. Chem., 2017, 224, 1-19.
[33]
Ikura, M.; Clore, G.M.; Gronenborn, A.M.; Zhu, G.; Klee, C.B.; Bax, A. Solution structure of a calmodulin-target peptide complex by multidimensional NMR. Science, 1992, 256(5057), 632-638.
[34]
Clore, G.M.; Bax, A.; Ikura, M.; Gronenborn, A.M. Structure of calmodulin-target peptide complexes. Curr. Opin. Struct. Biol., 1993, 3, 838-845.
[35]
Meador, W.E.; Means, A.R.; Quiocho, F.A. Target enzyme recognition by calmodulin: 2.4 Å structure of a calmodulin-peptide complex. Science, 1992, 257(5074), 1251-1255.
[36]
Fallon, J.L.; Halling, D.B.; Hamilton, S.L.; Quiocho, F.A. Structure of calmodulin bound to the hydrophobic IQ domain of the cardiac Ca(v)1.2 calcium channel. Structure, 2005, 13(12), 1881-1886.
[37]
Van Petegem, F.; Chatelain, F.C.; Minor, D.L., Jr Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex. Nat. Struct. Mol. Biol., 2005, 12(12), 1108-1115.
[38]
Lau, S.Y.; Procko, E.; Gaudet, R. Distinct properties of Ca2+–calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. J. Gen. Physiol., 2012, 140(5), 541-555.
[39]
Aoyagi, M.; Arvai, A.S.; Tainer, J.A.; Getzoff, E.D. Structural basis for endothelial nitric oxide synthase binding to calmodulin. EMBO J., 2003, 22(5), 766-775.
[40]
Ikura, M.; Barbato, G.; Klee, C.B.; Bax, A. Solution structure of calmodulin and its complex with a myosin light chain kinase fragment. Cell Calcium, 1992, 13(6-7), 391-400.
[41]
Osawa, M.; Tokumitsu, H.; Swindells, M.B.; Kurihara, H.; Orita, M.; Shibanuma, T.; Furuya, T.; Ikura, M. A novel target recognition revealed by calmodulin in complex with Ca2+-calmodulin-dependent kinase kinase. Nat. Struct. Biol., 1998, 6(9), 819-824.
[42]
Juranic, N.; Atanasova, E.; Filoteo, A.G.; Macura, S.; Prendergast, F.G.; Penniston, J.T.; Strehler, E.E. Calmodulin wraps around its binding domain in the plasma membrane Ca2+ pump anchored by a novel 18-1 motif. J. Biol. Chem., 2010, 285(6), 4015-4024.
[43]
Maximciuc, A.A.; Putkey, J.A.; Shamoo, Y.; Mackenzie, K.R. Complex of calmodulin with a ryanodine receptor target reveals a novel, flexible binding mode. Structure, 2006, 14(10), 1547-1556.
[44]
Cao, P.; Zhang, W.; Gui, W.; Dong, Y.; Jiang, T.; Gong, Y. Structural insights into the mechanism of calmodulin binding to death receptors. Acta Crystallogr. D Biol. Crystallogr., 2014, 70(6), 1604-1613.
[45]
Kurokawa, H.; Osawa, M.; Kurihara, H.; Katayama, N.; Tokumitsu, H.; Swindells, M.B.; Kainosho, M.; Ikura, M. 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., 2001, 312(1), 59-68.
[46]
Bayley, P.M.; Findlay, W.A.; Martin, S.R. Target recognition by calmodulin: dissecting the kinetics and affinity of interaction using short peptide sequences. Protein Sci., 1996, 5(7), 1215-1228.
[47]
Lee, K.; Alphonse, S.; Piserchio, A.; Tavares, C.D.J.; Giles, D.H.; Wellmann, R.M.; Dalby, K.N.; Ghose, R. Structural basis for the recognition of eukaryotic elongation factor 2 kinase by calmodulin. Structure, 2016, 24(9), 1441-1451.
[48]
Patel, N.; Stengel, F.; Aebersold, R.; Gold, M.G. Molecular basis of AKAP79 regulation by calmodulin. Nat. Commun., 2017, 8(1), 1681.
[49]
Ye, Q.; Li, X.; Wong, A.; Wei, Q.; Jia, Z. Structure of calmodulin bound to a calcineurin peptide: A new way of making an old binding mode. Biochemistry, 2006, 45(3), 738-745.
[50]
Ye, Q.; Wang, H.; Zheng, J.; Wei, Q. JIa, Z. The complex structure of calmodulin bound to a calcineurin peptide. Proteins, 2008, 73(1), 19-27.
[51]
Majava, V.; Kursula, P. Domain swapping and different oligomeric States for the complex between calmodulin and the calmodulin-binding domain of calcineurin a. PLoS One, 2009, 4(4)e5402
[52]
Köster, S.; Pavkov-Keller, T.; Kühlbrandt, W.; Yildiz, Ö. Structure of human Na+/H+ exchanger NHE1 regulatory region in complex with calmodulin and Ca2+. J. Biol. Chem., 2011, 286(47), 40954-40961.
[53]
Vlach, J.; Samal, A.B.; Saad, J.S. Solution structure of calmodulin bound to the binding domain of the HIV-1 matrix protein. J. Biol. Chem., 2014, 289(12), 8697-8705.
[54]
Johnson, C.N.; Potet, F.; Thompson, M.K.; Knollmann, B.C.; George, A.L., Jr; Chazin, W.J. A mechanism of calmodulin modulation of the human cardiac sodium channel. Structure, 2018, 26(5), 683-694.
[55]
Sarhan, M.F.; Tung, C.C.; Van Petegem, F.; Ahem, C.A. Crystallographic basis for calcium regulation of sodium channels. Proc. Natl. Acad. Sci. USA, 2012, 109(9), 3558-3563.
[56]
Potet, F.; Chagot, B.; Anghelescu, M.; Viswanathan, P.C.; Stepanovic, S.Z.; Kupershmidt, S.; Chazin, W.J.; Balser, J.R. Functional interactions between distinct sodium channel cytoplasmic domains through the action of calmodulin. J. Biol. Chem., 2009, 284(13), 8846-8854.
[57]
Bernardo-Seisdedos, G.; Nuñez, E.; Gomis-Perez, C.; Malo, C.; Villarroel, Á.; Millet, O. Structural basis and energy landscape for the Ca2+ gating and calmodulation of the Kv7.2 K+ channel. Proc. Natl. Acad. Sci. USA, 2018, 115(10), 2395-2400.
[58]
Sachyani, D.; Dvir, M.; Strulovich, R.; Tria, G.; Tobelaim, W.; Peretz, A.; Pongs, O.; Svergun, D.; Attali, B.; Hirsch, J.A. Structural basis of a Kv7.1 potassium channel gating module: Studies of the intracellular c-terminal domain in complex with calmodulin. Structure, 2014, 22(11), 1582-1594.
[59]
Strulovich, R.; Tobelaim, W.S.; Attali, B.; Hirsch, J.A. Structural insights into the M-channel proximal C-terminus/calmodulin complex. Biochemistry, 2016, 55(38), 5353-5365.
[60]
Gifford, J.L.; Ishida, H.; Vogel, H.J. Structural insights into calmodulin-regulated L-selectin ectodomain shedding. J. Biol. Chem., 2012, 287(32), 26513-26527.
[61]
Schmidt, A.; Kalkhof, S.; Ihling, C.; Cooper, D.M.; Sinz, A. Mapping protein interfaces by chemical cross-linking and Fourier transform ion cyclotron resonance mass spectrometry: Application to a calmodulin / adenylyl cyclase 8 peptide complex. Eur. J. Mass Spectrom. (Chichester, Eng.), 2005, 11(5), 525-534.
[62]
Dimova, K.; Kalkhof, S.; Pottratz, I.; Ihling, C.; Rodriguez-Castaneda, F.; Liepold, T.; Griesinger, C.; Brose, N.; Sinz, A.; Jahn, O. Structural insights into the calmodulin-Munc13 interaction obtained by cross-linking and mass spectrometry. Biochemistry, 2009, 48(25), 5908-5921.
[63]
Chavez, J.D.; Liu, N.L.; Bruce, J.E. Quantification of protein–protein interactions with chemical cross-linking and mass spectrometry. J. Proteome Res., 2011, 10(4), 1528-1537.
[64]
Schulz, D.M.; Ihling, C.; Clore, G.M.; Sinz, A. Mapping the topology and determination of a low-resolution three-dimensional structure of the calmodulin-melittin complex by chemical cross-linking and high-resolution FTICRMS: Direct demonstration of multiple binding modes. Biochemistry, 2004, 43(16), 4703-4715.
[65]
Irene, D.; Huang, J.W.; Chung, T.Y.; Li, F.Y.; Tzen, J.T.; Lin, T.H.; Chyan, C-L. Binding orientation and specificity of calmodulin to rat olfactory cyclic nucleotide-gated ion channel. J. Biomol. Struct. Dyn., 2013, 31(4), 414-425.
[66]
Dunlap, T.B.; Guo, H.F.; Cook, E.C.; Holbrook, E.; Rumi-Masante, J.; Lester, T.E.; Colbert, C.L.; Vander Kooi, C.W.; Creamer, T.P. Stoichiometry of the calcineurin regulatory domain-calmodulin complex. Biochemistry, 2014, 53(36), 5779-5790.
[67]
Chyan, C-L.; Irene, D.; Lin, S-M. The Recognition of Calmodulin to the Target Sequence of Calcineurin—A Novel Binding Mode. Molecules, 2017, 22(10)e1584
[68]
Chen, L.T.; Liang, W.X.; Chen, S.; Li, R.K.; Tan, J.L.; Xu, P.F.; Luo, L.F.; Wang, L.; Yu, S.H.; Meng, G.; Li, K.K.; Liu, T.X.; Chen, Z.; Chen, S.J. Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish. Nat. Commun., 2014, 5, 3811.
[69]
Chang, A.; Abderemane-Ali, F.; Hura, G.L.; Rossen, N.D.; Gate, R.E. Minor. D.L. Jr. A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function. Neuron, 2018, 97(4), 836-852.
[70]
Grishaev, A.; Anthis, N.J.; Clore, G.M. Contrast-matched small-angle x-ray scattering from a heavy-atom-labeled protein in structure determination: Application to a lead-substituted calmodulin–peptide complex. J. Am. Chem. Soc., 2012, 134(36), 14686-14689.
[71]
Piazza, M.; Taiakina, V.; Guillemette, S.R.; Guillemette, J.G.; Dieckmann, T. Solution structure of calmodulin bound to the target peptide of endothelial nitric oxide synthase phosphorylated at Thr495. Biochemistry, 2014, 53(8), 1241-1249.
[72]
Zhang, Y.; Matt, L.; Patriarchi, T.; Malik, Z.A.; Chowdhury, D.; Park, D.K.; Renieri, A.; Ames, J.B.; Hell, J.W. Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release. EMBO J., 2014, 33(12), 1341-1353.
[73]
Keller, J.P. Solution of the structure of a calmodulin-peptide complex in a novel configuration from a variably twinned data set. Acta Crystallogr. D Biol. Crystallogr., 2017, 73, 22-31.
[74]
Chen, Y.; Clarke, O.B.; Kim, J.; Stowe, S.; Kim, Y.K.; Assur, Z.; Cavalier, M.; Godoy-Ruiz, R.; von Alpen, D.C.; Manzini, C.; Blaner, W.S.; Frank, J.; Quadro, L.; Weber, D.J.; Shapiro, L.; Hendrickson, W.A.; Mancia, F. Structure of the STRA6 receptor for retinol uptake. Science, 2016, 353(6302)aad8266
[75]
Piazza, M.; Dieckmann, T.; Guillemette, J.G. Structural studies of a complex between endothelial nitric oxide synthase and calmodulin at physiological calcium concentration. Biochemistry, 2016, 55(42), 5962-5971.
[76]
Marques-Carvalho, M.J.; Oppermann, J.; Munoz, E.; Fernandes, A.S.; Gabant, G.; Cadene, M.; Heinemann, S.H.; Schonherr, R.; Morais-Cabral, J.H. Molecular insights into the mechanism of calmodulin inhibition of the EAG1 potassium channel. Structure, 2016, 24(10), 1742-1754.
Related Journals
Protein & Peptide Letters
Related Books
Frontiers in Protein and Peptide Sciences
Article Metrics
34
6
1
1