spinqualitylabelsall models Structure of calmodulin (PDB entry 3CLN) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Calmodulin [1]^[1] is able to bind a large range of target molecules. This property is due to its particularly flexible structure that confers the capacity to change its conformation according to the concentration of calcium in the cell. 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 N-lobe and the C-lobe) linked by a flexible α-helix. Each lobe contains a pair of helix-loop-helix 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.

spinqualitylabelsall models Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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.

• Three-dimensional structure of apocalmodulin

In the absence of bound Ca²⁺, the helices of calmodulin pack so that their hydrophobic side chains are not exposed. In this form it is unable to interact with its targets^[2].

• Ca²⁺-bound calmodulin

Binding of Ca²⁺ to the four sites induces a large conformational change causing the terminal helices to expose hydrophobic surfaces and also a long central α-helical segment. Ca²⁺-bound calmodulin binds to its targets with high affinity (K_D≈10⁻⁹ mol.L⁻¹).

spinqualitylabelsall models Calmodulin bound to a target peptide Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

• 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.

Contents 1 CaMII kinase 2 Family members 3 External Resources 4 References 5 Proteopedia page contributors and editor

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

• Najl V Valeyev1, Declan G Bates1, Pat Heslop-Harrison1,2, Ian Postlethwaite1 and Nikolay V Kotov. Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach.BMC Systems Biology 2008, 2:48 doi:10.1186/1752-0509-2-48[2]

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

• Idil Apak Evans and Madeline A. Shea*. Energetics of Calmodulin Domain Interactions with the Calmodulin Binding Domain of CaMKII. Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109. Published in final edited form as:Proteins. 2009 July; 76(1): 47–61Proteins. doi:10.1002/prot.22317PMCID: PMC2924166NIHMSID: NIHMS130871[3]

• D. Brent Halling, Dimitra K. Georgiou, D. J. Black, Guojun Yang, Jennifer L. Fallon, F. Determinants in CaV1 Channels That Regulate the Ca2+ Sensitivity of Bound Calmodulin. J Biol Chem. 2009 July 24; 284(30): 20041–20051.Published online 2009 May 27. doi:10.1074/jbcM109.013326 PMCID: PMC2740430[4]

• 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

Proteopedia page contributors and editor

Tonazzini Saphia, Planchenault Charlène