Department of Physiology Seminar Series
Michael Forgac, Ph.D.
Professor
Department of Physiology
Tufts University School of Medicine
Boston, MA
Room 4AB100, Noon- 1:00pm, Thursday, February 2, 2006
Research Interest:
The focus of my laboratory is to understand the mechanism by which eukaryotic cells
regulate the pH of their intracellular (or vacuolar) compartments. Vacuolar acidification plays a
crucial role in a variety of cellular processes, including receptor-mediated endocytosis,
intracellular membrane traffic, macromolecular processing and degradation and coupled
transport. Vacuolar acidification is carried out by the vacuolar family of (H+)-ATPases (or VATPases), which have been identified in many intracellular compartments, including clathrincoated vesicles, endosomes, lysosomes and secretory vesicles. V-ATPases in the plasma
membrane of certain specialized cells have also been implicated in such processes as renal
acidification, bone resorption and tumor metastasis.
V-ATPases are multisubunit complexes of molecular weight 900 kDa which are composed of
two functional domains. The peripheral V1 domain is a 640 kDa complex that is responsible for
ATP hydrolysis while the integral V0 domain is a 260 kDa complex responsible for proton
translocation. Our work has focused on elucidating the structure, subunit function and regulation
of the V-ATPases from a number of sources, including clathrin-coated vesicles and yeast
vacuoles. We have employed both chemical modification and site-directed mutagenesis to
characterize the nucleotide binding sites of the V-ATPase and to identify residues which play an
important role in proton translocation. We have used both conventional and cysteine-mediated
cross-linking as well as electron microscopy to determine the arrangement of subunits in the VATPase complex and have probed the mechanism of coupling of proton transport and ATP
hydrolysis using mutagenesis.
With respect to regulation of vacuolar acidification, we are pursuing several possible
mechanisms that appear be employed in controlling V-ATPase activity in vivo. These include
reversible disulfide bond formation between conserved cysteine residues at the catalytic site,
control of assembly of the V1 and V0 domains and differential targeting of V-ATPases within the
cell. These studies should provide insight into how cells control this important intracellular
parameter.
Persons with disabilities who may need auxiliary aids or services are requested to contact Josie
Martinez at least 24 hours prior to this seminar so that appropriate arrangements can be made.
Department of Physiology: Josie Martinez
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