Education

Postdoctoral Fellow
University of Washington, Stanford University
Ph.D.
Cornell University, 1986

Areas of Interest

Research Interests

Macromolecular transport processes during pathogenesis

Translocation of macromolecules between cells is a major area of biomedical interest. The focus of study in this laboratory is a type IV secretion (T4S) system of Agrobacterium tumefaciens. This system is ancestrally related and functionally similar to bacterial conjugation systems, as well as recently described protein translocation systems used by bacterial pathogens during the course of infection This T4S system mediates transfer of diverse substrates including oncogenic DNA and other DNA in the form of nucleoprotein particles, and of protein monomers across the A. tumefaciens cell envelope. These substrates are delivered to a variety of phylogenetically-diverse target bacterial or eukaryotic cells through a process dependent on direct cell-to-cell contact. This T4S system, assembled from VirD4 and 11 VirB subunits, is an especially attractive system for detailed mechanistic studies of macromolecular transport because of the ease of manipulation of A. tumefaciens, the large numbers of strains, constructs, and other molecular tools at hand, and the wealth of information about it and closely related transfer systems. We also are developing studies of other T4S systems of Gram-negative and Gram-positive bacterial pathogens.

The overall goal of work in this laboratory is to describe in detailed mechanistic terms the dynamic processes required for biogenesis and function of T4S systems during infection. We use powerful in vivo technologies developed in this laboratory and other state-of-the art biochemical and structure-based approaches to define how DNA and protein substrates are recruited to and translocated through the T4S channels.

Questions of particular interest at this time include:

  1. How do three ATPase subunits energize machine assembly or function?
  2. How are substrates recruited to the secretion channel?
  3. What is the route of substrate transfer through the secretory apparatus?
  4. How do bacterial cells establish contact with bacterial or eukaryotic target cells to mediate intercellular substrate transfer?
  5. What are the cellular consequences of substrate trafficking in the host cell?