Regulation of ABC proteins functions through protein interactions: role of linker domains of ABCB1/C1 in modulating protein functions

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The transport of molecules across the cell membrane is required for the survival of all living organisms. Cells in a toxic environment must actively transport diffused toxins from inside the cell (lower concentration) to the outside (higher concentration) against the toxins' concentration gradients. This "Active Transport" of molecules is essential for survival and is costly to cells, as it requires the expenditure of energy in the form of ATP. One class of active membrane transporters, known as ABC transporters contain an ATP-Binding Cassette domain (or an ABC domain) that functions as an engine that utilizes ATP to cause the transport of molecules across the cell membrane. It is now recognized that the ABC-transporters are one of the largest family of membrane proteins that are found in all living organisms from bacterial to man. The human genome encodes for 49 ABC proteins that are classified into seven subfamilies (ABC A - G). Research from several laboratories has shown these ABC proteins to transport various substrates, including chloride ions, glutathione, cholesterol, sterols, bile salts and many drugs, to name just few. Consequently, mutations affecting their normal functions have been shown to be causative of more than 17 genetic human disorders, such as cystic fibrosis (ABCC7) and Dubin-johnson syndrome (ABCC2). Some ABC transporters cause resistance to chemo-therapeutic drugs in cancer cells and in infectious organisms. Therefore, given the role of ABC transporters in health and disease conditions, they represent an important class of proteins "or enzymes" that must be tightly regulated by cells and organisms. The objectives of this proposal are to identify the proteins that interact with, and regulate the functions of these ABC transporters. Our recent work has identified one ABCB1 interacting protein. This protein binds to a specific domain of ABCB1 that is highly charged and of unknown function. Thus the identity and biologic significance of this and other ABCB1- and ABCC1-interacting proteins is the subject of this grant application. The results of this study should provide a novel approach to regulate or modulate the functions of ABC transporters and consequently a better understanding of the cellular pathways that can regulate ABC transporters.