Todd R. Graham, Ph.D.

Todd R. Graham, Ph.D.

Professor of Biological Sciences

Professor of Cell and Developmental Biology

2433 Stevenson Center
(615) 343-1835


We are interested in understanding how the cell assembles and maintains the ordered arrangement of membrane-bound compartments that compose the Golgi complex. We are also working to understand how the Golgi complex produces several different kinds of transport vesicles that deliver proteins to the cell surface, the endosomal/lysosomal system, the endoplasmic reticulum or newly forming Golgi cisternae.

B.A., Maryville College, St. Louis, MO
Ph.D., St. Louis University, St. Louis, MO
Postdoc, St. Louis University, St. Louis, MO
Postdoc, Caltech, Pasadena, CA
Postdoc, UCSD, San Diego, CA

Research Description

The Golgi complex of the eukaryotic cell plays a central role in the transport, modification, and sorting of proteins within the secretory pathway. We are interested in understanding how the cell assembles and maintains the ordered arrangement of membrane-bound compartments that compose the Golgi complex. We are also working to understand how the Golgi complex produces several different kinds of transport vesicles that deliver proteins to the cell surface, the endosomal/lysosomal system, the endoplasmic reticulum or newly forming Golgi cisternae. We are using the yeast Saccharomyces cerevisiae in these studies in order to apply the molecular genetic approaches that are possible with this organism.

ADP-ribosylation factor (ARF) is a small GTP binding protein that appears to mediate the formation of several different kinds of transport vesicles from Golgi membranes including both clathrin and COPI coated vesicles. In order to identify other proteins that function with ARF in vesicle-mediated protein transport, we have isolated mutations in several yeast genes (SWA1 i?? 7) that exhibit a synthetic lethal relationship with arf1 mutations. This genetic interaction suggests that the proteins encoded by the SWA genes functionally interact with ARF. Significantly, swa5-1 is a mutant allele of the yeast clathrin heavy chain gene and recent work suggests that other Swa proteins are involved in clathrin function. For example, Swa2p appears to be the yeast ortholog of auxilin, a neuronal protein that serves as a co-factor with Hsp70 in uncoating clathrin-coated vesicles.

SWA3 is allelic to DRS2 and encodes an integral membrane P-type ATPase that has been proposed to be an aminophospholipid translocase (or flippase). These enzymes flip phosphatidylserine (PS) or phosphatidylethanolamine (PE) from the extracellular (or lumenal) leaflet of the membrane to the cytosolic leaflet, and are thought to be responsible for the fact that PS and PE are restricted to the cytosolic leaflet of the plasma membrane in most eukaryotic cells. The identity of the aminophospholipid translocase is quite controversial but Swa3/Drs2p and related proteins remain the best candidates for this activity. We have found that Swa3/Drs2p localizes to trans-Golgi network (TGN) and is needed there to form a class of clathrin-coated vesicles that surprisingly carries exocytic cargo. The Swa3/Drs2p ATPase activity is necessary to support vesicle formation suggesting a potential role for lipid translocation in vesicle budding. Understanding the mechanism of Swa3/Drs2 contribution to vesicle budding continues to be a primary focus of the laboratory.

Drs2p is part of a family of potential yeast flippases that include Neo1, Dnf1, Dnf2 and Dnf3. We are systematically characterizing the role each yeast protein plays in vivo in order to gain a better understanding of their essential function. Human homologs of these proteins include ATPase II, ATP10C and FIC1. ATP10C is in a region of chromosome 15 implicated in a mental retardation disorder called Angelman syndrome, while mutations in FIC1 cause a genetic defect in bile secretion. At least 10 other genes encoding potential flippases are found in the human genome and very little is known about the cellular requirements for these proteins. We anticipate that our work on the yeast Drs2-family of ATPases will shed light on the function of this large family of potential flippases.

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