Structural biology of calcium channels

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***All living cells are surrounded by a barrier made out of oily lipids that serves to protect the integrity of the cell contents and isolate them from uncontrolled variations from the environment. The liposoluble membrane however limits the exchange or transfer of large molecules as well as small negatively and positively charged molecules (ions) which are needed by the cell for various activities including growth and reproduction. Life requires constant exchange between the extracellular and the intracellular media. In particular, fast biological responses result from the passage of ions that is catalyzed by the presence of aqueous pores that are formed by specialized membrane proteins called “ion channels”. The voltage-gated calcium channel is one of those ion channels that perform an essential biological task. This nanomachine is optimized to specifically carry calcium ions in the cell and must do so within strict limits because too much or too little calcium is lethal to the cell. This narrow range of operation could account in part for the complexity of this ion channel that is in fact made of multiple proteins interacting tightly within a macromolecular complex. These auxiliary proteins or subunits regulate the flow of ions. Some of these proteins increase the flow and some decrease the amount of ions going through the ion channel. It has been our long time goal of elucidate the nature of each of these auxiliary proteins and the nature of their interaction within the ion channel complex. To reach this goal, we have developed over the years specific tools in structural biology, biochemistry and biophysics to study these proteins. Research in my lab uses precise electrical recording techniques to study the movement of calcium, as they move through the calcium channel and across the cell membrane. We are also correlating the movement of calcium ions with changes in the primary and tri-dimensional structure of these proteins. Although most of these proteins have been known for more than 20 years, recent advances in the structural biology of these proteins last year have revealed a relatively unknown protein called the gamma subunit that may play a determinant role in the function of the skeletal muscle. The proposed research is thus aimed at understanding the nature and the specificity of the protein -protein interactions with the calcium channel in the skeletal muscle in order to better understand how this gamma subunit modulates calcium fluxes through the cell membrane. The proposed research will ultimately provide the structural basis underlying the tissue-specific protein networks responsible to conduct calcium ions through the cell membrane.