Biomedical Summer Undergraduate Research Experience Program
(B-SURE)
The University of Texas Health Science Center at San Antonio (UTHSCSA)
HART, P. John
(Biochemistry): Researchers in our laboratory combine the use of
single crystal X-ray diffraction with a wide range of molecular biological,
biochemical, and biophysical methods to characterize macromolecules of
fundamental biological and medicinal interest. The primary focus
of the lab is to understand the molecular basis for the inherited form
of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Laboratories
worldwide have sought to understand how point mutations in copper-zinc
superoxide dismutase (SOD1) render the protein toxic to motor neurons.
Our group has made significant strides in this area recently through our
examination of pathogenic SOD1 structure, where we find that many of the
mutants demonstrate conformational changes that give rise to non-native
SOD1-SOD1 protein-protein interactions that in turn lead to higher order,
amyloid-like filamentous assemblies. Because fibrillar aggregates
of pathogenic SOD1 are observed in FALS patients and murine models of the
disease, our crystallographic observations may represent the molecular
basis for pathogenic SOD1 aggregation in vivo. Future research is
aimed at probing the self-association properties of pathogenic SOD1 in
solution with an eye toward the development of novel therapeutics for the
disease.
An additional
area of interest includes structural studies on virulence factors from
Francisella tularensis. Francisella tularensis is considered
a Category A bioweapon due to the ease of transmission, the low infectious
dose and high mortality associated with pneumonic tularemia, and the fact
that it has been intensively studied and developed in bioweapons programs
in several countries. There is currently no vaccine approved for
general human use, rendering mankind at significant risk from the illicit
use of F. tularensis. Two F. tularensis gene products,
IglC and IglD, that are essential for virulence have been identified.
These proteins have no significant homology with any other known proteins,
and their exact function is currently unknown. However, they play
a role in evasion of killing within macrophages, an attribute that is critical
for Francisella’s ability to cause disease. Our structural
studies on these proteins will dramatically increase our knowledge of this
potential bioweapon and its mechanism of pathogenesis.
P. John Hart's Research
Group Web Page.
X-ray Crystallography
Facility Web Site.
Structure of a helical filament of SOD1