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Calmodulin is a well-known calcium binding protein (CaBP) composed of two domains, each containing two EF-hand motifs. These domains undergo a major conformational change upon binding two calcium ions, exposing a hydrophobic patch which is then able to interact with target proteins, transducing the calcium signal downstream. Calbindin D9k is a single-domain CaBP with high structural and sequence similarity to calmodulin, yet it does not undergo this major conformational change upon binding calcium. Thus it is referred to as a calcium signal "modulator" or "buffer", rather than a "sensor", like calmodulin.
Our research addresses the question of what factors, at an atomic level, determine whether an EF-hand CaBP acts as a signal modulator or sensor. This is being pursued through the design and creation of a hybrid molecule, 'calbindomodulin', which uses calbindin D9k as a base for rationally-chosen mutations intended to change its calcium-binding response such that it will undergo a major conformational change like calmodulin. The mutant proteins are expressed, purified, and characterized using a number of structural and biophysical techniques, including circular dichroism, fluorescence spectroscopy, mass spectrometry, X-ray crystallography, and NMR.
This slide show is a description of the project, which I presented to the Molecular Biophysics interest group at Vanderbilt on 19 August 2003.
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