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Clay Clark, PhD

Research Summary

Research in my lab focuses on the broad topics of caspase assembly and cell death.

We use procaspase-3 and procaspase-8 as representative members of the caspase family. Both proteins undergo maturation to yield mature, active proteases, but the mechanisms of activation are very different. Procaspase-3 is a stable dimer but has very little enzymatic activity, whereas procaspase-8 is a stable monomer that undergoes dimerization after association with death scaffolds.

We have shown that procaspase-3 can be activated allosterically through mutations in the dimer interface, and the constitutively active zymogen efficiently kills cancer cells. We use the information from biochemical and structural studies to develop small molecule drug compounds that activate procaspase-3. Research into allosteric activation of procaspases represents a new therapeutic approach to killing cancer cells.

Caspases are integral proteases in programmed cell death (apoptosis), and the dysregulation of apoptosis is observed in a number of human diseases, from autoimmune diseases (rheumatoid arthritis, diabetes, for example), to neurodegenerative diseases, to cancer. Learning to manipulate the levels of caspase activity in the cell could affect our understanding of many human diseases.

Further information is provided on the Research Projects link in the left panel.

Selected Publications

  1. Walters, J., Joshua L. Schipper, Paul Swartz, Carla Mattos and A. Clay Clark (2012). Allosteric modulation of caspases through mutagenesis. Bioscience Reports 32, 401-411.
  2. MacKenzie, Sarah H. & A. Clay Clark (2012) Death by caspase dimerization, in Protein Dimerization (and Oligomerization) in Biology, J. Matthews, ed., Landes Bioscience, 55-73.
  3. Schipper, Joshua L, Sarah H. MacKenzie, Anil Sharma & A. Clay Clark (2011) A bifunctional allosteric site in the dimer interface of procaspase-3. Biophysical Chemistry 159,100-109.
  4. Walters, Jad, Paul Swartz, Carla Mattos & A. Clay Clark (2011) Thermodynamic, enzymatic and structural effects of removing a salt bridge at the base of loop 4 in (pro)caspase-3. Archives of Biochemistry and Biophysics 508, 31-38.
  5. MacKenzie, Sarah H., Joshua L. Schipper & A. Clay Clark (2010) The potential for caspases in drug discovery. Current Opinion in Drug Discovery and Development 13, 568-576.

Keywords

Apoptosis, Cell Death, Caspases, Cancer Biology, Protein Assembly, Protein Engineering, Allosteric Activators, Drug Design, High-Throughput Drug Screening, Biochemistry and Biophysics, X-ray Crystallography, Spectroscopy, Transgenic Animals