The EF-hand family of Ca2+ binding proteins has a central role in many aspects of Ca2+ signal transduction pathways, from the regulation of the opening and closing of channels, to controlling the intensity and duration of Ca2+ signals, to the transduction of these signals into biochemical and biomechanical responses. Over 1000 EF-hand protein motifs have been identified from their unique sequence signatures. Yet despite their widespread distribution, very little is known about what features of their sequences provide them with their specific functions or what molecular mechanisms are used to distinguish among their diverse cellular targets. The objective of our research program is to define the molecular basis for the biochemical and biological function of EF-hand proteins, so that we may better understand their roles in health and disease. Ultimately, we will use this knowledge to alter or de novo design Ca2+-dependent cellular activities for medical and biotechnology applications. The overall objective of the current proposal is to answer two key questions regarding the underlying molecular basis for intracellular Ca2+ signal transduction: (i) How does the sequence of an EF-hand protein specify its response to the binding of Ca2+? (ii) How do different EF-hand proteins interact with and modulate specific protein targets? The first question will be addressed by a series of coupled mutagenesis, biophysical, and structural studies using calbindin D9k as a model system. A key goal in this work will be to create a new calbindin-calmodulin hybrid protein, calbindomodulin. The second question will be addressed by combined biophysical and structural studies seeking to determine the mechanisms of the Ca2+-induced activities of caltractin and the regulatory domain of the calcium dependent protein kinase. These results will link the large volume of experimental data available on EF-hand proteins, uncover the mechanisms by which these proteins function, and help to define their biological activities.
| Chazin, Walter J (2011) Relating form and function of EF-hand calcium binding proteins. Acc Chem Res 44:171-9 |
| Bunick, Christopher G; Miller, Michael R; Fuller, Brian E et al. (2006) Biochemical and structural domain analysis of xeroderma pigmentosum complementation group C protein. Biochemistry 45:14965-79 |
| Meyn, Susan M; Seda, Christina; Campbell, Muriel et al. (2006) The biochemical effect of Ser167 phosphorylation on Chlamydomonas reinhardtii centrin. Biochem Biophys Res Commun 342:342-8 |
| Sheehan, Jonathan H; Bunick, Christopher G; Hu, Haitao et al. (2006) Structure of the N-terminal calcium sensor domain of centrin reveals the biochemical basis for domain-specific function. J Biol Chem 281:2876-81 |
| Ortiz, Mildred; Sanoguet, Zuleika; Hu, Haitao et al. (2005) Dynamics of hydrogen-deuterium exchange in Chlamydomonas centrin. Biochemistry 44:2409-18 |
| Hu, Haitao; Sheehan, Jonathan H; Chazin, Walter J (2004) The mode of action of centrin. Binding of Ca2+ and a peptide fragment of Kar1p to the C-terminal domain. J Biol Chem 279:50895-903 |
| Bunick, Christopher G; Nelson, Melanie R; Mangahas, Sheryll et al. (2004) Designing sequence to control protein function in an EF-hand protein. J Am Chem Soc 126:5990-8 |
| Malmendal, Anders; Halpain, Shelley; Chazin, Walter J (2003) Nascent structure in the kinase anchoring domain of microtubule-associated protein 2. Biochem Biophys Res Commun 301:136-42 |
| Hu, Haitao; Chazin, Walter J (2003) Unique features in the C-terminal domain provide caltractin with target specificity. J Mol Biol 330:473-84 |
| Veeraraghavan, Sudha; Fagan, Patricia A; Hu, Haitao et al. (2002) Structural independence of the two EF-hand domains of caltractin. J Biol Chem 277:28564-71 |
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