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Calcium-free Calmodulin
Ca2+-Free Calmodulin
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Calmodulin is an intracellular calcium receptor found ubiquitously in eukaryotes.  It is capable of regulating biological activities of many cellular proteins and transmembrane ion transporters mainly in a Ca2+-dependent manner.  When the intracellular calcium level rises to 10-5 M, four Ca2+ ions bind to calmodulin, and this Ca2+-calmodulin complex binds the target proteins, initiating various signalling cascades.
Calmodulin has four EF-hand motifs that change conformation upon binding calcium ions. Each EF-hand motif contains two alpha helices connected by a 12-residue loop. The calcium ion binds to the loop region and changes the relative positions of the alpha helices (Yap et al, 1999). In absence of calcium, the alpha-helices in the EF-hand motif of calmodulin are positioned almost parallel to each other. This is known as the closed conformation.

Upon binding Ca2+, calmodulin undergoes large conformational changes. The crystal structure of Ca2+-loaded calmodulin exhibits a dumbbell shape (Babu et al., 1985, Babu et al., 1988). However, it was later found that part of the central linker region of Ca2+-bound calmodulin is flexible in solution (Barbato et al, 1992).
Calcium-bound Calmodulin
Ca2+-bound Calmodulin
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Both x-ray and NMR studies agree that the alpha helices of the EF-hand motifs change their position relative to each other, forming an almost perpendicular conformation (open conformation). This radical change allows calmodulin to increase its binding affinity for a number of target proteins. Gerstein and Krebs (1998) has a web site with movies that illustrate how calmodulin changes its conformation.

It has been shown through numerous structural studies that upon binding its target peptides, CaM forms a compact globular conformation by bending its central helix. Three calmodulin-binding peptides that have been studied so far (skeletal and smooth muscle myosin light chain kinases and calmodulin-dependent kinase II) form an alpha-helical conformation which passes through the middle of calmodulin, much like two hands holding onto a rope.
Peptide bound to Calcium-bound calmodulin
Ca2+-bound Calmodulinwith rabbit skMLCK
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peptide bound to calcium-bound calmodulin

A high content of methionine residues (9 out of 148 residues) in calmodulin have been believed to be responsible for the ability to bind numerous target proteins. Indeed, 8 of the 9 methionines are directly involved in binding to all target peptides studied so far by x-ray and NMR.

On this website, we present the IQ, 1-10, 1-14 and 1-16 motif classes and other motifs that have been identified through sequence homology analyses by various investigators and structural analyses that are available.
Please browse through the website. There are programs that predict whether a protein contains a calmodulin-binding sequence (prediction program), and calculate average hydrophobicity, average hydrophobic moment and average propensity for alpha-helix formation for a short peptide (analysis program). You may also browse the database that forms the basis of the prediction program.
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