Transcriptional repressor complexes and membrane proteins

Our research centers on the study of protein structure and molecular recognition, with an emphasis on understanding proteinprotein, protein-peptide and protein-lipid interactions. We use a variety of biophysical, bioinformatic and biochemical techniques to address these questions, including x-ray crystallography, spectroscopy and thermodynamic methods.

Structure and function of the BTB domain
Several human BTB-zinc finger proteins, including PLZF and BCL6, are transcriptional repressors that are implicated in development and/or in cancer. The BTB domain in these proteins represses the expression of target genes by the BTB-mediated recruitment of HDAC/corepressor complexes to promoter sites recognized by the C-terminal zinc-finger regions. We are studying the interactions of BTB domains with corepressor and cullinbased ubiquitin ligase complexes with the objective of developing protein-protein interaction inhibitors to reverse the biological activities of these oncogene products.

Structural biology of membrane proteins
It is widely recognized that new methods are needed for the structural study of membrane proteins, and we are addressing the problem of membrane protein crystallization by developing lipopeptide detergents (LPDs), a fundamentally different class of amphiphile designed specifically for the crystallization of membrane proteins. We are also studying the thermodynamics of membrane protein folding, and the fundamental properties of protein-lipid and protein detergent interactions. We have interests in several specific membrane and membrane-associated proteins, including transporters, the PagP acyl transferase, and the saposin proteins.

For more information visit our lab homepage at http://xtal.uhnres.utoronto.ca/prive/

Graduate Students:

• Hamed Ghanei
• Konstantin Popovic

Selected References:

• Parekh S, Privé GG and Melnick A. Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas. Leukemia and Lymphoma (2008).

• Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Privé GG. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Molecular Cell (2008).

• Michaux C, Pomroy NC, Privé GG. Refolding SDS-Denatured Proteins by the Addition of Amphipathic Cosolvents. J. Mol. Biol. (2008).

• Alattia JR, Shaw JE, Yip CM, Privé GG. Molecular imaging of membrane interfaces reveals mode of beta-glucosidase activation by saposin C. Proc. Natl. Acad. Sci. 104, 17388-17393 (2007).