Assistant Chairman, Department of Chemistry
University of Notre Dame
BS, State University of New York at Buffalo, 1982
PhD, State University of New York at Buffalo, 1990
Postdoctoral fellow, Brandeis University, 1990-1993
Postdoctoral fellow, University of Notre Dame, 1994-1997
Department of Chemistry & Biochemistry
University of Notre Dame
Notre Dame, IN 46556
W. M. Keck Center for Transgene Research
Phone: (574) 631-9120
Fax: (574) 631-6652
Honors and Awards
1982 BS, Magna Cum Laude
1986 Outstanding First Year Graduate Student
1987 Allied-Signal, Inc., Research Fellowship
1991-1993 National Institutes of Health Postdoctoral Research Fellowship
1994-1997 American Heart Association Postdoctoral Research Fellowship
2002 Associate Editor, Current Drug Targets
2005 Reviewer, NIH Special Emphasis Panel, Neuropharmacology Small Business
It has long been acknowledged that all of the information required for peptides and proteins to adopt their biologically active three-dimensional conformations is specified in the sequential arrangement of their constituent amino acids. However, the contribution of specific amino acids to the process of proper folding, a fundamental issue in structural biology, remains largely unanswered for a number of important proteins and peptides. A related question concerns the nature of the interactions between the folded species and their physiological targets. The relationship of peptide/protein structure to function and activity has been an important component of our research program for many years. Our laboratory is particularly interested in a class of peptides and proteins that contain a high relative content of a non-standard amino acid known as gamma-carboxyglutamic acid (Gla). These include many plasma proteins involved in blood coagulation and a class of neuroactive peptides, the conantokins, which are sourced in the venom of predatory marine snails and act as potent and specific antagonists of the N-methyl-D-aspartate receptor. We also investigate structure-function relationships in plasminogen, the principal effector of fibrinolysis, and the precursor of angiostatin, an inhibitor of tumor growth and proliferation.
In our laboratories, we evaluate the contributions of individual amino acids and groups of amino acids to proper conformation and function through two strategies; site-specific mutagenesis and peptide synthesis. The biophysical and structural properties of the peptides and proteins thus generated are characterized using a suite of methodologies including analytical ultracentrifugation, microcalorimetry, fluorimetry, X-ray crystallography, surface plasmon resonance, and circular dichroism and NMR spectroscopies. For functional assessments, our laboratory employs enzymology, radioligand binding, and electrophysiology. We also examine in vivo effects in mice. Taken together, these approaches permit us to pinpoint the often subtle structural features that influence the biological activity of the peptides and proteins under study.
Selected Recent Publications
Sheng Z, Prorok M, Brown BE, Castellino FJ. (2008). N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein. Neuropharm. 55:204-214.
Fu Q, Figuera-Losada M, Ploplis VA, Cnudde S, Geiger JH, Prorok M, Castellino FJ. (2008). The lack of binding of VEK-30, an internal peptide from the group A streptococcal M-like protein, PAM, to murine plasminogen is due to two amino acid replacements in the plasminogen kringle-2 domain. J Biol Chem. 28:1580-1587.
Sheng Z, Dai Q, Prorok M, Castellino FJ. (2007). Subtype-selective antagonism of N-methyl-D-aspartate receptor ion channels by synthetic conantokin peptides. Neuropharm. 53:145-156.
Dai Q, Sheng Z, Geiger JH, Castellino FJ, Prorok M. (2007). Helix-helix interactions between homo- and heterodimeric gamma-carboxyglutamate-containing conantokin peptides and their derivatives. J Biol Chem 282:12641-12649.
Cnudde SE, Prorok M, Castellino FJ, Geiger JH. (2006). The X-ray crystallographic structure of the angiogenesis inhibitor, angiostatin, bound to a peptide from the group A streptococcal surface protein PAM. Biochemistry. 45:11052-11060.
Wei J, Dong M, Xiao C, Jiang F, Castellino FJ, Prorok M, Dai Q. (2006). Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice. Neurosci Lett. 405:137-141.
Busquets L, Guillen H, DeFord ME, Suckow MA, Navari RE, Castellino FJ, and Prorok M. (2005). Cathepsin E is a specific marker of dysplasia in APCMin/+ mouse intestine. Tumor Biol. 27:36-42.
Dai Q, Prorok M, Castellino FJ. (2005). The role of the hexapeptide disulfide loop in the gamma-carboxyglutamic acid domain of protein C in Ca2+-mediated structural and functional properties. Biochemistry. 44:12508-12514.
Dai Q. Castellino FJ, Prorok M. (2004). A single amino acid replacement results in the Ca2+-induced self-assembly of a helical conantokin-based peptide. Biochemistry. 43:13225-13232.
Dai Q, Prorok M, Castellino, FJ. (2004). A new mechanism for metal ion-assisted interchain helix assembly in a naturally-occurring peptide mediated by optimally spaced gamma-carboxyglutamic acid residues. J Mol Biol. 336:731-744