A A Email Print Share

Michael Cascio

Associate Professor
Bayer School of Natural and Environmental Sciences
Chemistry and Biochemistry

331A Mellon Hall
Phone: 412.396.1894
casciom@duq.edu

Education:

Ph.D., Biochem. & Mol. Biophysics, Columbia University, 1988
M.A., Biochem. & Mol. Biophysics, Columbia University, 1984
B.A., Chemistry and Biology, Cornell University, 1981
Research

The major research interest of my laboratory is the correlation of structure and function for membrane protein receptors and channels, primarily neuroreceptors. Utilizing recent biotechnological advances, we successfully overexpressed recombinant human glycine receptors (hGlyRs) and rat serotonin transporters (rSERT) in insect cells at fairly high levels. The GlyR receptor is part of a superfamily of ligand-gated ion channels critical in transmission of synaptic signals. Using circular dichroism, and mass spectrometry coupled with chemical modification, we critically examined the topology and structure of this paradigmatic ion channel. In order to continue to characterize the structure of this ion channel, our lab is systematically incorporating cysteine residues at select regions of the receptor and incorporating non-specific crosslinking and cleavage reagents (to map accessibility and proximity using mass spectrometry as a structural tool), and fluorescent tags. Analogous studies are also being conducted on SERT, a paradigmatic member of the monoamine transporter superfamily. We are also engaged in studies examining the effects of lipid composition on the structure and function of these receptors, and these studies are an outgrowth of our lipidomics-based studies wherein we are developing novel methodologies to identify and quantitate bioactive lipids. We are developing novel mass spectrometry-based tools to complement high resolution methods such as nmr and x-ray crystallography, with a particular focus on examining membrane protein allostery.


 

Courses
2009 - present Director and lecturer CHEM 401/501 Biochemistry I
2010 - present Organizer CHEM 588 Research in Progress
2011 - present      Director and lecturer CHEM 527 Biochem. Biophys. Char. Macromol.
2012, 2017 Director and lecturer      CHEM 402/502      Biochemistry II
2013, 2015, 2018 Co-Director and lecturer CHEM 425 Integrated Lab II
2011 - present Director CHEM 588 Research in Progress
2016 Director and lecturer CHEM 541 Structural Proteomics
2017 - present Director and lecturer CHEM 419 Advanced Biochemistry I
2016 - present Director CHEM 691 Seminar Series
Publications
Refereed articles

1. Cascio, M. and Wallace, B.A. (1984) Effects of Environment on the Conformation of the Alamethicin Membrane Channel. Ann. N.Y. Acad. Sci. 435, 527-529.

2. Wallace, B.A., Cascio, M., and Mielke, D.L. (1986) Evaluation of Prediction Methods for Membrane Protein Secondary Structures. Proc. Natl. Acad. Sci. (USA), 83, 9423-9427.

3. Cascio, M. and Wallace, B.A. (1989) Conformation of Alamethicin in Phospholipid Vesicles: Implication for Insertion Models. Proteins 4, 89-99.

4. Cascio, M., Glazer, P.A., and Wallace, B.A. (1989) The Secondary Structure of Human Amyloid Deposits as Determined by Circular Dichroism Spectroscopy. Biochem. Biophys. Res. Comm. 162, 1162-1166.

5. Cascio, M., Gogol, E., and Wallace, B.A. (1990) The Secondary Structure of Gap Junctions: Influence of Isolation Methods and Proteolysis. J. Biol. Chem. 265, 2358-2364.

6. Cascio, M., Schoppa, N.E., Grodzicki, R.L., Sigworth, F.J., and Fox, R.O.(1993) Expression and Purification of a Homomeric Human 1 Glycine Receptor in Baculovirus-Infected Insect Cells. J. Biol. Chem. 268, 22135-22142.

7. Cascio, M. and Wallace, B.A. (1994) Red- and Blue-Shifting in the Circular Dichroism Spectra of Polypeptides Due to Dipole Effects. Protein and Peptide Lett. 1, 136-140.

8. Cascio, M. and Wallace, B.A. (1995) Effects of Local Environment on the Circular Dichroism Spectra of Polypeptides. Analytical Biochem. 227, 90-100.

9. Cascio, M., Kumar, N.M., R. Safarik, and Gilula, N.B. (1995) Physical Characteristics of Gap Junction Membrane Connexons (Hemi-Channels) Isolated from Rat Liver. J. Biol. Chem. 270, 18643-18648.

10. Chakraborty, A., Dyer, K.F., Cascio, M., Mietzner, T.A., and Tweardy, D.J. (1999) Identification of a Novel Stat3 Recruitment Motif within the Granulocyte Colony-Stimulating Factor Receptor. Blood 93:15-24.

11. Leite, J., Amoscato, A., and Cascio, M. (2000) Coupled Proteolytic and Mass Spectrometry Studies Indicate Novel Topology for Glycine Receptor. J. Biol. Chem. 275:13683-13689.

12. Leite, J. and Cascio, M. (2001) Structure of the Ligand-Gated Ion Channel Superfamily: Critical Assessment of Biochemical Data Supports Novel Topology. Mol. Cell. Neurosci. 17, 777-792.

13. Cascio, M., Shenkel, S., Grodzicki, R.L., Sigworth, F.J., and Fox, R.O. (2001) Functional Reconstitution and Characterization of Recombinant Human 1 Glycine Receptors. J. Biol. Chem. 276, 20981-20988.

14. Leite, J.F. and Cascio, M. (2002) Probing the Topology of the Glycine Receptor by Chemical Modification Coupled to Mass Spectrometry. Biochemistry 41, 6140-6148.

15. Leite, J.F., Gribble, B., Randolph, N., and Cascio, M. (2002) In vitro Interaction of the Glycine Receptor with the Leptin Receptor. Physiology and Behavior 77, 565-569.

16. Cascio, M. (2002) Glycine Receptors: Lessons on Topology and Structural Effects of the Lipid Bilayer. Biopolymers 66, 359-368.

17. Cascio, M. and Rapaka, R. (2002) Structural Biology and Structural Genomics/Proteomics. J. Peptide Research. 60, 307-311.

18. Tseng, C.-N., Zhang, L., Cascio, M., and Wang, Z.Z. (2003) Calcium Plays a Critical Role in Determining the Acetylcholine Receptor-clustering Activities of Alternatively Spliced Isoforms of Agrin. J. Biol. Chem. 278, 17236-17245.

19. Tillman, T. and Cascio, M. (2003) Effects of Lipids on Ion Channel Structure and Function. Cell Biochemistry and Biophysics 38, 161-190.

20. Cascio, M., Mayor, J.A., and Kaplan, R.S. (2004) Analysis of the Secondary Structure of the Cys-less Yeast Mitochondrial Citrate Transport Protein and Four Single-Cys Variants by Circular Dichroism. J. Bioenerg. Biomembr. 36, 429-438.

21. Kim, S.I., Voshol, H., van Oostrum, J., Hastings, T.G., Cascio, M., and Glucksman, M.J. (2004) Neuroproteomics - Expression Profiling of the Brain's Proteomes in Health and Disease. Neurochem. Res. 29, 1317-1331.

22. Shangary, S., Oliver, C.L, Tillman ,T.S., Cascio, M., and Johnson D.E. (2004) Sequence and Helicity Requirements for the Proapoptotic Activity of Bax BH3 peptides. Mol. Cancer Ther. 3, 1343-1354.

23. Deslouches, B., Phadke, S.M., Lazarevic, V., Cascio, M., Islam, K., Montelaro, R.C., Mietzner ,T.A. (2005) De novo Generation of Cationic Antimicrobial Peptides: Influence of Length and Tryptophan Substitution on Antimicrobial Activity. Antimicrob. Agents Chemother. 49, 316-322.

24. Alajez, N.M., Schmielau, J., Alter, M.D., Cascio, M., and Finn, O.J. (2005) Therapeutic Potential of a Tumor Specific, MHC-unrestricted T Cell Receptor expressed on Effector Cells of the Innate and Adaptive Immune Systems through Bone Marrow transduction and Immune Reconstitution. Blood 15, 4583-4589 (cover feature).

25. Cheng, M.H., Cascio, M., and Coalson, R.D. (2005) Theoretical Studies of the M2 Transmembrane Segment of the Glycine Receptor: Models of the Open Pore Structure and Current-Voltage Characteristics. Biophys. J. 89, 1669-1680 (cover feature).

26. Speranskiy, K. Cascio, M., and Kurnikova, M. (2007) Homology model and Molecular Dynamics Simulations of the Glycine Receptor ligand binding Domain. Proteins 67, 950-960.

27. Iyer, A.K.V., Tran, K.T., Borysenko, C.W., Cascio, M., Camacho, C.J., Blair, H.C., Bahar, I., and Wells, A. (2007) Tenascin Cytotactin Epidermal Growth Factor-Like Repeat Binds Epidermal Growth Factor Receptor with Low Affinity. J. Cell. Physiol. 211, 748-758.

28. Cheng, M.H., Cascio, M., and Coalson, R.D. (2007) Homology Modeling and Molecular Dynamics Simulation of the Transmembrane Domain of the Human 1 Glycine Receptor. Proteins. 68, 581-593.

29. Srinivasan, R., Huang, S., Chaudry, S., Sculptoreanu, A., Krisky, D., Cascio, M., Friedman, P.A., de Groat, W.C., Wolfe, D., and Glorioso, J.C. (2007) An HSV Vector System for Selection of Ligand-gated Ion Channel Modulators. Nature Methods. 4, 733-739.

30. Zhang, B.-S., Sun, C., Cascio, M. and Montelaro, R.C. (2008) Mapping of Equine Lentivirus Receptor-1 Residues Critical for EIAV Envelope Binding. J. Virol. 82, 1204-1213.

31. Cheng, M.H., Coalson, R.D. and Cascio, M., (2008) Molecular Dynamics Simulations of Ethanol Binding to the Transmembrane Domain of the Glycine Receptor: Implications for the Channel Potentiation Mechanism. Proteins. 71, 972-81.

32. Van Laar V.S., Dukes A.A., Cascio M., and Hastings T.G. (2008) Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: Implications for Parkinson disease. Neurobiology of Disease. 29, 477-489.

33. Dukes A.A., Van Laar V.S., Cascio M., and Hastings T.G. (2008) Changes in endoplasmic reticulum stress proteins and aldolase A in cells exposed to dopamine. J. Neurochem. 106, 333-346.

34. Liu, Z., Ramanoudjame, G., Liu, D., Fox, R.O., Jayaraman, V., Kurnikova, M., and Cascio, M. (2008) Overexpression and Functional Characterization of a Mutated Form of the Extracellular Domain of Human Homomeric 1 Glycine Receptor. Biochemistry. 47, 9803-9810.

35. Cheng, M.H., Coalson, R.D. Cascio, M., and Kurnikova, M. (2008) Computational Prediction of Ion Permeation Characteristics in the Glycine Receptor Modified by Photo-sensitive Compounds. J. Comput. Aided Mol. Des. 22, 563-570.

36. Van Laar V.S., Mishizen A.J., Cascio M., and Hastings T.G. (2009) Proteomic Identification of Dopamine-conjugated Proteins from Isolate Rat brain Mitochondria and SH-SY5Y Cells. Neurobiol. Disease. 34, 467-500.

37. Ruthstein, S., Stone, K.M., Cunningham, T., Cascio, M., and Saxena, S. (2010) Pulsed Electron Spin Resonance resolves the coordination site of Cu+2 in a1-Glycine Receptor. Biophys. J. 99, 2497-2506.

38. Tseng, C.-N., Zhang, L., Wu, S,-L., Wang, W.-F., Wang, Z.Z., and Cascio, M. (2010) Asparagine of z8 insert is critical for the affinity, conformation and acetylcholine receptor-clustering activity of neural agrin. J. Biol. Chem. 285, 27641-27651.

39. Jameel, N.M., Thirunavukkarasu, C., Murase, N., Cascio, M., Prelich, J., Yang, S., Harvey, S.A.K., and Gandhi, C.R. (2010) Constitutive release of powerful antioxidant-scavenging activity by hepatic stellate cells: protection of hepatocytes from ischemia/reperfusion injury. Liver Transpl. 16, 1400-1409.

40. Goss, J.R.*, Cascio, M.*, Goins, W.F., Huang, S., Krisky, D.M., Clarke, R.C., Johnson, J.W., Yoshimura, N., Gold, M.S., and Glorioso, J.C. (2011) HSV delivery of a ligand-regulated endogenous ion channel gene to sensory neurons results in pain control following channel activation. Molecular Therapy. 19, 500-506.
*co-first authors

41. Divito, E.B., Davic, A.P., Johnson, M.E., and Cascio, M. (2012) Electrospray ionization and collision induced dissociation mass spectrometry of primary fatty acid amides. Anal Chem. 84, 2388-2294.

42. Janjic, J.M., Patel, S.K., Patrick, M.J., Pollock, J.A., DiVito, E.B., and Cascio, M. (2013) Suppressing inflammation from inside out with novel NIR visible perfluorocarbon nanotheranostics. Proceedings of SPIE (International Society for Optics and Photonics). Volume. 8596: Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications V (Eds: Achilefu, S. and Raghavachari, R.). 85960L.

43. Pope, D., Madura, J., and Cascio M. (2014) β-Amyloid and neprilysin computational studies identify critical residues implicated in binding specificity. J. Chem. Inf. Model. 54, 1157-65.

44. Liu, Z., Szarecka, A., Yonkunas, M., Speranskiy, K., Kurnikova, M., and Cascio, M. (2014) Crosslinking constraints and computational models as complementary tools in modeling the extracellular domain of the glycine receptor. PLOS One. 9, e102571.

45. Divito, E.B., Davic, A.P., Kroniser, K.M., and Cascio, M. (2016) Multidimensional liquid chromatography coupled with tandem mass spectrometry for identification of bioactive fatty acyl derivatives. Frontiers Physiol. 7:608 doi: 10.3389/fphys.2016.00608

46. Ferraro N.A and Cascio M. (2018) Cross-Linking-Mass Spectrometry Studies of Cholesterol Inter-actions with Human α1 Glycine Receptor. Anal Chem. 90, 2508-2516. doi: 10.1021/acs.analchem.7b03639.

Invited articles, reviews and book chapters

1. Divito E.B. and Cascio, M. (2013) Metabolism, Physiology, and Analyses of Primary Fatty Acid Amides. Chemical Reviews. 13, 7343-7353.

2. Pope, D. and Cascio, M. (2014) Neprilysin Inhibitors Provide Insight into the Specificity of the Enzyme and its Potential for Alzheimer's Disease Therapy. Frontiers in Drug Design and Discovery. 6, 598-622.

3. Kotermanski, S.E. and Cascio, M. (2016) Neuronal action potentials and ion channel allostery. In: Ralph A Bradshaw and Philip D Stahl (Editors-in-Chief), Encyclopedia of Cell Biology, (Waltham, MA: Academic Press,) 1, 244-251. doi:10.1016/B978-0-12-394447-4.10028-8.