Dr. VanDemark received his Ph.D. in 2001 with Cynthia Wolberger at Johns Hopkins University, performed his postdoctoral research with Christopher Hill at the University of Utah, and joined the Department in 2007.
We use a variety of biochemical and structural techniques including X-ray crystallography to discover the molecular mechanisms that describe how proteins functions and how their activities are disrupted in the disease state. We have active research interests in the following areas:
GDAP1
GDAP1 (Ganglioside-induced differentiation-associated protein 1) is a novel member of the ancient GST superfamily of detoxification enzymes. Most GST enzymes are cytosolic dimeric enzymes that recognize electrophilic lipids such as oxidized and damaged lipids or xenobiotic substrates. Conjugation of cellular glutathione to these substrates facilitates their removal, and thus they are playing a cytoprotective cellular role. GDAP1, however, appears to have evolved a different role: it does not bind glutathione, is monomeric, and is localized to the mitochondria where it appears to play a non-enzymatic role in mitochondrial dynamics and membrane organization, the cellular response to oxidative stress, and maintenance of the cellular redox state. Nearly a hundred missense mutations in GDAP1 have been identified which cause the neuropathy Charcot-Marie-Tooth (CMT), the most common peripheral neuropathy. CMT currently has no cure and the mechanism underlying the root cause of the disease just like GDAP1’s function is unknown.
We are trying to address this by revealing the molecular mechanisms underlying GDAP1 function. Current projects in the lab are focused on:
- Identifying the range of lipids or other hydrophobic cargo that can be recognized within the GDAP1 active site pocket
- Revealing the functional consequences of lipid binding (does GDAP1 facilitate their transport or instead use them as signaling molecules?)
- Examining the structural and biophysical changes concomitant with loading of lipid onto GDAP1.
- Describing the range of GDAP1-mediated protein-protein interactions and their role in driving functions associated with GDAP1.
TPI Deficiency
Triose Phosphate Isomerase (TPI; also known as TIM1) is an essential glycolytic enzyme that performs the interconversion of dihydroxyacetone phosphate (DHAP) and glycerol-3-phosphate (G3P). Mutations in TPI are rare but result in TPI Deficiency (TPI Df), characterized by severe hemolytic anemia, neuromuscular disorders and defects, and cardiomyopathies. As new TPI Df are identified, we are part of a team that is characterizing the molecular basis of their disease, examining the impact of the mutant on protein stability, enzymatic activity, the proteins biophysical features and its ability to bind substrate, product, and inhibitors.
Pfn1
Profilin 1, is an actin-binding protein well known for its ability to regulate the formation of actin filaments within the cell in response to cellular and physiological cues. The actin cytoskeleton (and thus the activity of Pfn1) has been shown to play an important role in angiogenic responses in the wake of ocular injuries and in numerous cancers. We are part of a collaborative team seeking to rationally design and improve novel inhibitors of the Pfn1-actin interaction through biochemical characterization of Pfn1 inhibitor binding interactions and through structural elucidation of Pfn1-inhibitor complexes.