David Domingo Sabatini, Ph.D., Doc. en Med.

Research Summary
Research in this laboratory is primarily concerned with the mechanisms by which newly synthesized proteins are targeted to their sites of function in different membranes and organelles. We have had long-standing interest in the rough endoplasmic reticulum (ER) and, in particular, the translocation apparatus that in this organelle effects the insertion into the membrane and the cotranslational modification of nascent secretory, lysosomal, and membrane polypeptides. Currently, our research focuses on the sorting processes that occur in the trans region of the Golgi apparatus, and select different subsets of proteins for incorporation into vesicles that deliver them to developing secretory granules, lysosomes, or the different domains of the plasma membrane of polarized epithelial cells. For these studies, we have developed a cell-free system in which we can reproduce in vitro the generation of post Golgi vesicles from isolated Golgi fractions that contain a viral glycoprotein on its way to the cell surface. This has allowed us to undertake the identification and purification of the cytosolic and membrane proteins (including vesicle coat proteins, GTP-binding proteins, protein kinases, phospholipases, and phospholipid transport proteins) that participate in protein sorting, vesicle formation, and vesicle targeting to the acceptor membrane.

We are also studying the role of GTP-binding proteins of the rab family in the vectorial transport of proteins to the apical and basolateral plasma membrane domains of epithelial cells and in the recycling of plasma membrane receptors that follows their interiorization by endocytosis. We have identified and cloned a protein kinase that binds specifically to the GTP-bound form of rab8, a protein involved in Golgi to basolateral membrane transport, and are attempting to determine the specific biochemical role of the kinase. We have also identified and cloned a protein that binds specifically to the GTP-bound form of rab11, and have obtained evidence that rab11 and its binding protein control fusion of early endosomes and the return of receptors from recycling endosomes to the cell surface.

List Of Publications