STRUCTURAL BIOLOGY OF EF-HAND CALCIUM BINDING PROTEINS

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION: Calcium and calcium-binding proteins, (CABPS) play a central role in cellular signal transduction pathways and are associated with a wide-range of effects on health and disease. At the functional level, Cal-mediated, cellular events include cell growth and differentiation, cell cycle progression, apoptosis and metabolic control. This research program seeks an understanding of how CaBPs work at the molecular level, to develop the ability to control binding properties and utlimately, to design specific biological activities and therapeutic strategies relevant to calcium-mediated disease. To attain this goaL the three-dimensional structures and internal dynamics of specific CaBPs are being determined in the presence and absence of Ca2+ using NMR spectroscopy. The responses to binding Ca2+ are then compared for different.CaBPs across the spectrum of their biological activities. One phase of our research involves extending the range of the CaBP database to caltracin. This protein is an essential component of the microtubule organizing center in the centrosome which is required for accurate chromosomal segregation during the M (mitosis) stage of the cell cycle. It's unique properties. including phosphorylation in-vivo apparently in a cell cycle-dependent manner, make it an extremely attractive target for therapeutic intervention But comparison between different proteins is not suffficient to explain how and why functional and structural differences occur. This level of understanding requires fundamental knowledge of the driving forces and molecular details of Ca2+ binding and the concomitant changes induced in protein structure and dynamics. To address these issues, the second phase of our research involves calbindin D 9k, an EF-hand CaBP that has been characterized at an unprecedented level of detail. Studies of the protein's structure and dynamics at the highest possible resolution, in combination with site-directed mutagenesis and protein engineering experiments, are being used to piece together a complete picture of the molecular basis for Ca2+ affinity, selectivity, cooperativity and the transmission of these binding properties into a diverse range of biological activities.