Calmodulin [1] The calmodulin structure has been determined by NMR. This method reveals that calmodulin is a long molecule which looks like a dumbbell because it contains two globular domains (the and the ) linked by a . Each lobe contains a pair of motifs (called EF-hand) that can bind two Ca²⁺ ions. However those lobes do not have the same properties because the C-lobe has higher Ca²⁺ affinity than the N-lobe. The two EF-hands are located in the vicinity of each other. Those neighboring sited are very likely to structurally influence each other upon Ca²⁺ binding to one of them.

The affinity of the individual Ca²⁺ ion binding sites are in the range 10⁻⁵-10⁻⁶ mol.L⁻¹ and adjacent sites bind Ca²⁺ with positive cooperativity, so that attachment of the first Ca²⁺ ion enhances the affinity of its neighbour. This has the effect of making the protein sensitive to small changes in the concentration of Ca²⁺ within the signaling range. Ca²⁺-calmodulin itself has no intrinsic catalytic activity. Its action depends on its close association with a target enzyme.

2+</sup>-bound calmodulin'Ca²⁺-bound calmodulin'/>

• Calmodulin bound to a target peptide

To form the bound state, the central residues of the link region unwind form their α-helical arrangement to form a hinge that allows the molecule to bend and wrap itself around the target. The N-terminal and C-terminal regions approach each other and by their hydrophobic surfaces bind to it, rather like two hands holding a rope. This encourages the target sequence to adopt an α-helical arrangement so that it occupies the center of a hydrophobic tunnel. The consequence of this interaction is a conformational change in the target, a state that persists only as long as the Ca²⁺ concentration remains high.

When the Ca²⁺ concentration falls, calcium dissociates and calmodulin is quickly released, inactivating the target. However, at least one important target protein is an exception to this rule. This is CaM-kinase II which can retain its active state after it has been activated by calmodulin.

CaMII kinase

Calmodulin plays an important role through kinase enzymes such as calcium/calmodulin-dependent kinase II (CaMKII) that is a multifunctional serine/threonine kinase found in many tissues. Activation of CaMKII contributes to synaptic plasticity and regulation of excitory synaptic transmission. The regulatory domain of CaMKII contains an autophosphorylation site, which is essential for its calcium-dependent activation.

Family members

• Calmodulin 1 (CALM1)
• Calmodulin 2 (CALM2)
• Calmodulin 3 (CALM3)
• Calmodulin-like 1 (CALML1)
• Calmodulin-like 3 (CALML3)
• Calmodulin-like 4 (CALML4)
• Calmodulin-like 5 (CALML5)
• Calmodulin-like 6 (CALML6)

External Resources

• Protein Data Bank file on 2CLP
• Biochimie générale 10ième édition. Jacques-Henri Weil 2005
• Signal Transduction Gomperts.Kramer.Tatham Seconde edition

References

• Valeyev NV, Bates DG, Heslop-Harrison P, Postlethwaite I, Kotov NV. Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach. BMC Syst Biol. 2008 Jun 2;2:48. PMID:18518982 doi:10.1186/1752-0509-2-48

• Fallon JL, Quiocho FA. A closed compact structure of native Ca(2+)-calmodulin. Structure. 2003 Oct;11(10):1303-7. PMID:14527397

• Evans TI, Shea MA. Energetics of calmodulin domain interactions with the calmodulin binding domain of CaMKII. Proteins. 2009 Jul;76(1):47-61. PMID:19089983 doi:10.1002/prot.22317

• Halling DB, Georgiou DK, Black DJ, Yang G, Fallon JL, Quiocho FA, Pedersen SE, Hamilton SL. Determinants in CaV1 channels that regulate the Ca2+ sensitivity of bound calmodulin. J Biol Chem. 2009 Jul 24;284(30):20041-51. Epub 2009 May 27. PMID:19473981 doi:10.1074/jbc.M109.013326

• Colbran RJ, Brown AM. Calcium/calmodulin-dependent protein kinase II and synaptic plasticity. Curr Opin Neurobiol. 2004 Jun;14(3):318-27. PMID:15194112 doi:10.1016/j.conb.2004.05.008

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