Primary Research Interests
- Kinases and phosphatases that produce inositol phosphate and phosphatidylinositol signals
- Protein chemistry
- Structural biology
My lab combines biochemical and structural techniques to study kinases and phosphatases that produce soluble inositol phosphate (IP) and membrane-bound phosphatidylinositol (PI) signals in cells. Inositol-based signalling is ubiquitous in human cells and its dysregulation has been linked with disease states. Our goal is to understand how these kinases and phosphatases produce highly specific inositol signals and how they elicit their effects in cells. To do this, we study the structures of IP- and PI- kinases and phosphatases, their catalytic mechanisms, and how their actions are regulated in the cell. We use x-ray crystallography to determine high-resolution structures of these enzymes and protein engineering to correlate the structure of each enzyme with its catalytic function and their downstream effects. We also use proteomics to identify cellular interactions between these enzymes with other proteins, which provides a cellular context for their actions. Using these approaches we generate a clear understanding of the functions of these kinases and phosphatases and we also obtain high-resolution structures to facilitate inhibitor design efforts to target inositol-based signalling networks.
Machkalyan, G., Hébert, TE, and Miller, GJ. (2016) PPIP5K1 Suppresses Etoposide-triggered apoptosis. Submitted.
Machkalyan, G., Trieu, P., Pétrin, D., Hébert, TE, and Miller, GJ. (2016). Mass spectrometry analysis of PPIP5K1 interactions and data on cell motility of PPIP5K1-deficient cells. Data in Brief. 7: 443-1446.
Machkalyan, G., Trieu, P., Pétrin, D., Hébert, TE, and Miller, GJ. (2016). PPIP5K1 interacts with the exocyst complex through a C-terminal intrinsically disordered domain and regulates cell motility. Cell Signal. 2016 Feb 15;28(5):401-411.
Khan, SM, Sleno, R, Gors, S, Zybergold, P, Laverdure, JP, Labbé, Miller GJ, Hébert,TE (2013). The expanding roles of Gβγ subunits in G protein-coupled receptor signaling and drug action. Pharmacol Rev 13, 545-77.
Gosein, V., Leung, T-F., Krajden, O., Miller, G.J. (2012). Inositol phosphate-induced stabilization of inositol 1,3,4,5,6-pentakisphosphate 2-kinase and its role in substrate specificity. Protein Science 21(5), 737-42.
Lamba, P., Wang, Y., Tran, S., Ouspenskaia, T., Libasci, V., Hébert, T.E., Miller, G.J.,Bernard, D.J. (2010). Activin A regulates porcine follicle-stimulating hormone β subunit transcription via cooperative actions of SMADs and FOXL2. Endocrinology 151(11), 5456-67.
Quiniou, C., Sapieha, P., Lahaie, I., Hou, X., Brault, S., Beauchamp, M., Leduc, M., Rihakova, L., Joyal, J-S., Nadeau, S., Heveker, N., Lubell, W., Sennlaub, F., Gobeil, F., Miller, G., Pshezhetsky, A., Chemtob, S. (2008). Development of a novel non-competitive antagonist of interleukin-1 receptor. Journal of Immunology 180, 6977-6987.
Miller, G.J., Wilson, M.P., Majerus, P.W., and Hurley, J.H. (2005). Specificity determinants in inositol polyphosphate synthesis: crystal structure of inositol 1,3,4-trisphosphate 5/6-kinase. Molecular Cell 18, 201-212.
Miller, G.J., and Hurley, J.H. (2004). Crystal structure of the catalytic core of inositol 1,4,5-trisphosphate 3-kinase. Molecular Cell 15, 703-711.
Miller, G.J., Mattera, R., Bonifacino, J.S., and Hurley, J.H. (2003). Recognition of accessory protein motifs by the gamma-adaptin ear domain of GGA3. Nature Structural Biology 10, 599-606.
Hurley, J.H., Anderson, D.E., Beach, B., Canagarajah, B., Ho, Y.S., Jones, E., Miller, G., Misra, S., Pearson, M., Saidi, L., et al. (2002). Structural genomics and signaling domains. Trends in Biochemical Sciences 27, 48-53.
Misra, S., Miller, G.J., and Hurley, J.H. (2001). Recognizing phosphatidylinositol 3- phosphate. Cell 107, 559-562.
CHEM 109: General, Organic, and Biochemistry for the Health Sciences
CHEM 119: General, Organic, and Biochemistry for the Health Sciences Lab
CHEM 127: Biochemistry of Science Fiction
CHEM 128: Food Meets Science – Biochemistry of Food and Cooking
CHEM 405: Science Communication
CHEM 471: Biochemistry I
CHEM 472: Biochemistry II
CHEM 493: Undergraduate Research
CHEM 496: Biochemical Techniques
BIOL 544: Enzymology