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Calmodulin

From EverybodyWiki Bios & Wiki


Calmodulin is a small, highly conserved protein that is 148 amino acids long (16.7 kDa). The protein has two approximately symmetrical globular domains (the N- and C- domains) each containing a pair of EF hand motifs[1] separated by a flexible linker region for a total of four Ca2+ binding sites, two in each globular domain.[2] In the Ca2+-free state, the helices that form the four EF-hands are collapsed in a compact orientation, and the central linker is disordered;[3] separated by a flexible linker region for a total of four Ca2+ binding sites, two in each globular domain.[4][5][6] in the Ca2+-saturated state, the EF-hand helices adopt an open orientation roughly perpendicular to one another, and the central linker forms an extended alpha-helix in the crystal structure,[7][8] but remains largely disordered in solution.[9] The C-domain has a higher binding affinity for Ca2+ than the N-domain.[10][11]

Calmodulin is structurally quite similar to troponin C, another Ca2+-binding protein containing four EF-hand motifs.[12][13] However, troponin C contains an additional alpha-helix at its N-terminus, and is constitutively bound to its target, troponin I. It therefore does not exhibit the same diversity of target recognition as does calmodulin.

Importance of flexibility in calmodulin[edit]

Calmodulin’s ability to recognize a tremendous range of target proteins is due in large part to its structural flexibility.[14] In addition to the flexibility of the central linker domain, the N- and C-domains undergo open-closed conformational cycling in the Ca2+-bound state.[15] Calmodulin also exibits great structural variability,[16] and undergoes considerable conformational fluctuations,[17][18] when bound to targets. Moreover, the predominantly hydrophobic nature of binding between calmodulin and most of its targets allows for recognition of a broad range of target protein sequences.[19][20] Together, these features allow calmodulin to recognize some 300 target proteins[21] exhibiting a variety of CaM-binding sequence motifs.

Mechanism[edit]

This images shows conformational changes in calmodulin. On the left is calmodulin without calcium and on the right is calmodulin with calcium. Sites that bind target proteins are indicated by red stars.
Solution structure of Ca2+-calmodulin C-terminal domain
Solution structure of Ca2+-calmodulin N-terminal domain

Binding of Ca2+ by the EF-hands causes an opening of the N- and C-domains, which exposes hydrophobic target-binding surfaces.[22] These surfaces interact with complementary nonpolar segments on target proteins, typically consisting of groups of bulky hydrophobic amino acids separated by 10-16 polar and/or basic amino acids.[23][24] The flexible central domain of calmodulin allows the protein to wrap around its target, although alternate modes of binding are known. “Canonical” targets of calmodulin, such as myosin light-chain kinases and CaMKII, bind only to the Ca2+-bound protein, whereas some proteins, such as NaV channels and IQ-motif proteins, also bind to calmodulin in the absence of Ca2+.[25] Binding of calmodulin induces conformational rearrangements in the target protein via “mutually induced fit”,[26] leading to changes in the target protein’s function. Calcium binding by calmodulin exhibits considerable cooperativity,[27][28][29] making calmodulin an unusual example of a monomeric (single-chain) cooperative-binding protein. Furthermore, target binding alters the binding affinity of calmodulin toward Ca2+ ions,[30][31][32] which allows for complex allosteric interplay between Ca2+ and target binding interactions.[33] This influence of target binding on Ca2+ affinity is believed to allow for Ca2+ activation of proteins that are constitutively bound to calmodulin, such as small-conductance Ca2+-activated potassium (SK) channels.[34]

Proposed changes to "structure" and "mechanism" sections of Calmodulin article[edit]


This article "Calmodulin" is from Wikipedia. The list of its authors can be seen in its historical and/or the page Edithistory:Calmodulin. Articles copied from Draft Namespace on Wikipedia could be seen on the Draft Namespace of Wikipedia and not main one.

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  1. ↑ Gifford, J.L.; Walsh, M.P.; Vogel, H.J. (2007). "Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs". Biochemical Journal. 405 (2): 199–221. doi:10.1042/BJ20070255. PMID 17590154.
  2. ↑ Chin, D.; Means, A.R. (2000). "Calmodulin: A prototypical calcium sensor". Trends in Cell Biology. 10 (8): 322–328. doi:10.1016/s0962-8924(00)01800-6. PMID 10884684.
  3. ↑ Gifford, J.L.; Walsh, M.P.; Vogel, H.J. (2007). "Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs". Biochemical Journal. 405 (2): 199–221. doi:10.1042/BJ20070255. PMID 17590154.
  4. ↑ Chin, D.; Means, A.R. (2000). "Calmodulin: A prototypical calcium sensor". Trends in Cell Biology. 10 (8): 322–328. doi:10.1016/s0962-8924(00)01800-6. PMID 10884684.
  5. ↑ Kuboniwa, H.; Tjandra, N.; Grzesiek, S.; Ren, H.; Klee, C.B.; Bax, A. (1995). "Solution structure of calcium-free calmodulin". Nature Structural Biology. 2 (9): 768–776. doi:10.1038/nsb0995-768. PMID 7552748. Unknown parameter |s2cid= ignored (help)
  6. ↑ Zhang, M.; Tanaka, T.; Ikura, M. (1995). "Calcium-induced conformational transition revealed by the solution structure of apo calmodulin". Nature Structural Biology. 2 (9): 758–767. doi:10.1038/nsb0995-758. PMID 7552747. Unknown parameter |s2cid= ignored (help)
  7. ↑ Gifford, J.L.; Walsh, M.P.; Vogel, H.J. (2007). "Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs". Biochemical Journal. 405 (2): 199–221. doi:10.1042/BJ20070255. PMID 17590154.
  8. ↑ Chin, D.; Means, A.R. (2000). "Calmodulin: A prototypical calcium sensor". Trends in Cell Biology. 10 (8): 322–328. doi:10.1016/s0962-8924(00)01800-6. PMID 10884684.
  9. ↑ Chou, J.J.; Li, S.; Klee, C.B.; Bax, A. (2001). "Solution structure of Ca2+-calmodulin reveals flexible hand-like properties of its domains". Nature Structural Biology. 8 (11): 990–997. doi:10.1038/nsb1101-990. PMID 11685248. Unknown parameter |s2cid= ignored (help)
  10. ↑ Yang, J.J.; Gawthrop, A.; Ye, Y. (2003). "Obtaining site-specific calcium-binding affinities of calmodulin". Protein and Peptide Letters. 10 (4): 331–345. doi:10.2174/0929866033478852. PMID 14529487.
  11. ↑ Linse, S.; Helmersson, A.; Forsen, S. (1991). "Calcium binding to calmodulin and its globular domains". Journal of Biological Chemistry. 266 (13): 8050–8054. PMID 1902469.
  12. ↑ Gifford, J.L.; Walsh, M.P.; Vogel, H.J. (2007). "Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs". Biochemical Journal. 405 (2): 199–221. doi:10.1042/BJ20070255. PMID 17590154.
  13. ↑ Houdousse, A.; Love, M.L.; Dominguez, R.; Grabarek, Z.; Cohen, C. (1997). "Structures of four Ca2+-bound troponin C at 2.0 Å resolution: further insights into the Ca2+-switch in the calmodulin superfamily". Structure. 5 (12): 1695–1711. doi:10.1016/s0969-2126(97)00315-8. PMID 9438870.
  14. ↑ Yamniuk, A.P.; Vogel, H.J. (2004). "Calmodulin's flexibility allows for promiscuity in its interactions with target proteins and peptides". Molecular Biotechnology. 27 (1): 33–57. doi:10.1385/MB:27:1:33. PMID 15122046. Unknown parameter |s2cid= ignored (help)
  15. ↑ Chou, J.J.; Li, S.; Klee, C.B.; Bax, A. (2001). "Solution structure of Ca2+-calmodulin reveals flexible hand-like properties of its domains". Nature Structural Biology. 8 (11): 990–997. doi:10.1038/nsb1101-990. PMID 11685248. Unknown parameter |s2cid= ignored (help)
  16. ↑ Tidow, H.; Nissen, P. (2013). "Structural diversity of calmodulin binding to its target sites". FEBS Journal. 280 (21): 5551–5565. doi:10.1111/febs.12296. PMID 23601118.
  17. ↑ Frederick, K.K.; Marlow, M.S.; Valentine, K.G.; Wand, A.J. (2007). "Conformational entropy in molecular recognition by proteins". Nature. 448 (7151): 325–330. Bibcode:2007Natur.448..325F. doi:10.1038/nature05959. PMC 4156320. PMID 17637663.
  18. ↑ Gsponer, J.; Christodoulou, J.; Cavalli, A.; Bui, J.M.; Richter, B.; Dobson, C.M.; Vendruscolo, M. (2008). "A coupled equilibrium shift mechanism in calmodulin-mediated signal transduction". Structure. 16 (5): 736–746. doi:10.1016/j.str.2008.02.017. PMC 2428103. PMID 18462678.
  19. ↑ Tidow, H.; Nissen, P. (2013). "Structural diversity of calmodulin binding to its target sites". FEBS Journal. 280 (21): 5551–5565. doi:10.1111/febs.12296. PMID 23601118.
  20. ↑ Ishida, H.; Vogel, H.J. (2006). "Protein-peptide interaction studies demonstrate the versatility of calmodulin target peptide binding". Protein and Peptide Letters. 13 (5): 455–465. doi:10.2174/092986606776819600. PMID 16800798.
  21. ↑ "Calmodulin Target Database". Retrieved 27 July 2020.
  22. ↑ Chin, D.; Means, A.R. (2000). "Calmodulin: A prototypical calcium sensor". Trends in Cell Biology. 10 (8): 322–328. doi:10.1016/s0962-8924(00)01800-6. PMID 10884684.
  23. ↑ "Calmodulin Target Database". Retrieved 27 July 2020.
  24. ↑ Tidow, H.; Nissen, P. (2013). "Structural diversity of calmodulin binding to its target sites". FEBS Journal. 280 (21): 5551–5565. doi:10.1111/febs.12296. PMID 23601118.
  25. ↑ Tidow, H.; Nissen, P. (2013). "Structural diversity of calmodulin binding to its target sites". FEBS Journal. 280 (21): 5551–5565. doi:10.1111/febs.12296. PMID 23601118.
  26. ↑ Wang, Q.; Zhang, P.; Hoffman, L.; Tripathi, S.; Homouz, D.; Liu, Y.; Waxham, M.N.; Cheung, M.S. (2013). "Protein recognition and selection through conformational and mutually induced fit". Proceedings of the National Academy of Sciences of the USA. 110 (51): 20545–20550. Bibcode:2013PNAS..11020545W. doi:10.1073/pnas.1312788110. PMC 3870683. PMID 24297894.
  27. ↑ Gifford, J.L.; Walsh, M.P.; Vogel, H.J. (2007). "Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs". Biochemical Journal. 405 (2): 199–221. doi:10.1042/BJ20070255. PMID 17590154.
  28. ↑ Linse, S.; Helmersson, A.; Forsen, S. (1991). "Calcium binding to calmodulin and its globular domains". Journal of Biological Chemistry. 266 (13): 8050–8054. PMID 1902469.
  29. ↑ Linse, S.; Helmersson, A.; Forsen, S. (1991). "Calcium binding to calmodulin and its globular domains". Journal of Biological Chemistry. 266 (13): 8050–8054. PMID 1902469.
  30. ↑ Johnson, J.D.; Snyder, C.; Walsh, M.; Flynn, M. (1996). "Effects of myosin light chain kinase and peptides on Ca2+ exchange with the N- and C-terminal Ca2+-binding sites of calmodulin". Journal of Biological Chemistry. 271 (2): 761–767. doi:10.1074/jbc.271.2.761. PMID 8557684. Unknown parameter |s2cid= ignored (help)
  31. ↑ Bayley, P.A.; Findlay, W.A.; Martin, S.R. (1996). "Target recognition by calmodulin: Dissecting the kinetics and affinity of interaction using short peptide sequences". Protein Science. 5 (7): 1215–1228. doi:10.1002/pro.5560050701. PMC 2143466. PMID 8819155.
  32. ↑ Theoharis, N.T.; Sorensen, B.R.; Theisen-Toupal, J.; Shea, M.A. (2008). "The neuronal voltage-dependent sodium channel type II IQ motif lowers the calcium affinity of the C-domain of calmodulin". Biochemistry. 47 (1): 112–123. doi:10.1021/bi7013129. PMID 18067319.
  33. ↑ Stefan, M.I.; Edelstein, S.J.; Le Novere, N. (2008). "An allosteric model of calmodulin explains differential activation of PP2B and CamKII". Proceedings of the National Academy of Sciences of the USA. 105 (31): 10768–10773. Bibcode:2008PNAS..10510768S. doi:10.1073/pnas.0804672105. PMC 2504824. PMID 18669651.
  34. ↑ Zhang, M.; Abrams, C.; Wang, L.; Gizzi, A.; He, L.; Lin, R.; Chen, Y.; Loll, P.J.; Pascal, J.M.; Zhang, J.-F. (2012). "Structural basis for calmodulin as a dynamic calcium sensor". Structure. 20 (5): 911–923. doi:10.1016/j.str.2012.03.019. PMC 3372094. PMID 22579256.

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