Sandbox 213: Difference between revisions
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=Structure= | =Structure= | ||
Calmodulin 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 RMN. 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. | Calmodulin [http://www.rcsb.org/pdb/101/motm_disscussed_entry.do?id=3cln]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 RMN. 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. | ||
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. | 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. | ||
Revision as of 15:11, 21 December 2011
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Calmodulin (CaM) is an important protein that intervenes in a wide range of activities. Indeed, it is a small (16.7 kDa=148 aa) and highly conserved protein that is necessary in all eukaryotic cells because it represents an essential calcium sensor with troponin C its isoform. Calmodulin contains four Ca2+ binding sites and the binding of calcium induces a conformational change in calmodulin that can cause the activation of key enzymes such as kinases or phosphatases proteins (especially phosphorylase kinases) which are not necessarily themselves Ca2+-sensitive and allows a large diversity of cellular response.
StructureStructure
Calmodulin [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 RMN. 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. 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.
- 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 (KD ≈10-9 mol.L-1).
- 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 kinaseCaMII 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.
External ResourcesExternal Resources
- Protein Data Bank file on 2CLP
- Biochimie générale 10ième édition. Jacques-Henri Weil 2005
- Signal Transduction Gomperts.Kramer.Tatham Seconde edition
ReferencesReferences
1. ↑Najl V Valeyev1*, Declan G Bates1, Pat Heslop-Harrison1,2, Ian Postlethwaite1 and Nikolay V Kotov3. 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]
2. ↑Fallon JL, Quiocho FA.Structure. 2003 Oct;11(10):1303-7.A closed compact structure of native Ca(2+)-calmodulin.Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. [3]
3. ↑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): 47–61. [4]
4. ↑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 [5]
5. ↑Colbran RJ, Brown AM. Calcium/calmodulin-dependent protein kinase II and synaptic plasticity.Curr Opin Neurobiol. 2004 Jun;14(3):318-27. Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615, USA. roger.colbran@vanderbilt.edu [6]
Proteopedia Page Contributors and EditorProteopedia Page Contributors and Editor
Saphia TONAZZINI, Charlène PLANCHENAULT