We are interested in how viruses hijack the ubiquitin-proteasome pathway to suppress innate immunity. A paradigmatic example of this phenomenon is provided by the primate lentiviral Vif protein and its suppression of the antiviral gene APOBEC3G. In this seminar, I will outline our 20-year odyssey aimed at understanding the mechanism of the primate lentiviral Vif protein. This problem is important because APOBEC3G acts as a barrier for cross-species transmission of primate lentiviruses while adaptations in Vif gave rise to the birth of HIV-1 and the AIDS pandemic. We recently determined the cryoEM structure of HIV-1 Vif bound to APOBEC3G and discovered RNA is a cofactor for the interaction. We show that APOBEC3G binding to Vif is not restricted to the evolutionary dynamic interface predicted by genetic studies, but rather, also includes a conserved interface through RNA binding that helps position key residues necessary for viral antagonism of a host antiviral gene. The structural and functional studies suggest Vif binds APOBEC3G in its most dangerous form for the virus, when bound to genomic RNA en route to packaging. This work reveals that virus-host interaction interfaces may be far larger than what is gleaned from modeling genetic signatures of molecular arms races onto protein surfaces, an important consideration for drug-discovery.
What I do:
I am interested in protein structure and dynamics related to gene expression. We study changes in protein structure that occur on time scales ranging from millions of years to a millionth of a second, with a focus on basic questions of how viruses cross-species and give rise to modern pandemics or how enzyme function is fine-tuned by cellular cues. Research in this area guides development of therapeutics for infectious disease and cancer.
Departmental research area:
Physical biology
My research expertise:
NMR spectroscopy, structural biology, enzymology
Professional background:
Degrees:
PhD, Physical Chemistry, Massachusetts Institute of Technology (MIT), 1998
BS, Chemistry, Sewanee: The University of the South, 1992
Biography:
We investigate molecular machines that coordinate gene expression or antiviral immunity. Research areas include: i- RNA decay enzymes that act in mRNA quality control and gene regulatory pathways, and ii- nucleic acid based immune systems that protect animals from viruses and neutralization of these systems by viral accessory proteins. We use tools from molecular biophysics to understand the structure and regulatory conformational dynamics in these systems with the ultimate goal of defining molecular mechanisms and avenues for structure based drug design.
Research keywords:
Schizosaccharomyces pombe Proteins
RNA, Fungal
vif Gene Products, Human Immunodeficiency Virus
Endoribonucleases
Cytosine Deaminase
APOBEC-3G Deaminase
RNA Stability
RNA Caps
Gene Products, vif
RNA-Binding Proteins
Schizosaccharomyces
Cytidine Deaminase
Cullin Proteins
RNA, Messenger
Saccharomyces cerevisiae Proteins