Sandbox 213: Difference between revisions

'''Calmodulin''' [http://www.rcsb.org/pdb/101/motm_disscussed_entry.do?id=3cln]  

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.

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 <scene name='Sandbox_213/N-lobe/1'>N-lobe</scene> and the <scene name='Sandbox_213/C-lobe/1'>C-lobe</scene>) linked by a <scene name='Sandbox_213/flexible α-helix/1'>flexible α-helix</scene> <ref name="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]]"/>.

Each lobe contains a pair of <scene name='Sandbox_213/helix-loop-helix/1'>helix-loop-helix</scene> motifs (called EF-hand or calmodulin-fold) 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.  

This presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices (BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The flexibility of Calmodulin's hinged region allows the molecule to "wrap around" its target. This property allows it to tightly bind to a wide range of different target proteins. <ref name="Houdusse A, Gaucher JF, Krementsova E, Mui S, Trybus KM, 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 U S A. 2006 Dec 19;103(51):19326-31. Epub 2006 Dec 6. PMID :[[17151196]]"/>. </StructureSection>

*'''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.The C-terminal lobe of each CaM adopts a semi-open conformation that grips the first part of the IQ motif (IQxxxR), whereas the N-terminal lobe adopts a closed conformation that interacts more weakly with the second part of the motif (GxxxR). <ref name="Houdusse A, Gaucher JF, Krementsova E, Mui S, Trybus KM, 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 U S A. 2006 Dec 19;103(51):19326-31. Epub 2006 Dec 6. PMID:[[17151196]]"/>.

[[Image:Calmodulin bound to calcium.png|right|100px]]

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 <ref name="Fallon JL, Quiocho FA. A closed compact structure of native Ca(2+)-calmodulin. Structure. 2003 Oct;11(10):1303-7. PMID :[[14527397]]"/>.

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=