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Brief Biography

Dr. Julie Deborah Forman-Kay received her BSc specializing in chemistry, from the Massachusetts Institute of Technology in 1985. In 1990, she received her PhD in molecular biophysics & biochemistry from Yale University under the supervision of Dr. Fred Richards. 

Forman-Kay completed her post-doctoral studies at the Laboratory of Chemical Physics at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health in Bethesda, Maryland in 1992. Her supervisors were Marius Clore & Angela Gronenborn. In 1992, she joined The Hospital for Sick Children (SickKids) and the Department of Biochemistry at the University of Toronto.

Research Interests

• Disordered states of proteins
• Protein interactions
• Protein motion
• Protein structure
• Structure-function relationships

Research Activities

Structural and Dynamic Studies of Protein Complexes:

We are interested in understanding the basis for sequence-specific protein recognition in the regulation of biological processes, including signal transduction. We have characterized SH2, SH3, PTB and WW domains with their targets and have described "non-canonical" modes of binding from structure of complexes as well as energetic details of the interface based on dynamics and binding experiments. We are now moving towards more detailed studies of the thermodynamic and kinetic effects of disordered target regions in interactions showing cooperativity or avidity. In addition, we are studying a number of multi-domain enzymes, including Eph kinase and the Smurf2 ubiquitin ligase, in order to probe the regulatory effects of intramolecular protein interactions.

Unfolded State of an SH3 domain:

In the absence of peptides derived from its binding target SOS, the N-terminal SH3 domain of the Drosophila drk protein is in equilibrium between folded and unfolded states. We have characterized the structure and dynamics of this unfolded state, which is highly populated under non-denaturing solution conditions, using NMR and other spectroscopic methods and find it to be quite distinct from a theoretical random coil with significant native-like and some non-native residual structure. Insights into protein folding have been derived from our studies. We have exploited this protein as a model system in our development of a computational approach (ENSEMBLE) to facilitate a more quantitative characterization of unfolded and other disordered states and continue to refine this methodology.

Disordered States of Proteins:

The primary sequence motifs that are targets for modular binding domain interaction are located within intrinsically disordered protein regions. Other disordered regions contain binding targets that adopt more complex structure upon binding. Disordered regions of proteins have been recognized as important for mediating protein recognition in regulation, with almost half of eukaryotic proteins having significant stretches of disorder. We are characterizing a number of these intrinsically disordered regions of proteins, including those implicated in signal transduction. These include gamma-synuclein (a marker for breast cancer), Sic1 (a cyclin dependent kinase inhibitor), the regulatory (R) region of CFTR, the N-terminal portion of the prion protein and its homologue Shadoo and 4E-BP2 (part of the translation initiation machinery). Knowledge of: (i) the polymer chain characteristics of these proteins; (ii) the thermodynamic and structural properties of both free and complexed states; and (iii) the range of dynamics remaining in complexes involving disordered proteins is critical for understanding how disordered proteins function in protein recognition.

Domains of CFTR:

An additional area of interest in my lab is the cytoplasmic regions of CFTR in order to better understand the gating and regulation of function of this chloride channel. In addition to the disordered regulatory R region mentioned above, there are nucleotide binding domains NBD1 and NBD2, with NBD1 being the site of the most common CF mutation, the N-terminal helix and the intracellular loop (ICL) regions. We are currently characterizing the structural, dynamic and interaction properties of the NBD1, NBD2, R region and ICL peptides using NMR methods. We are also probing interactions of these regions with CF therapeutic compounds.

External Funding

• Canadian Institutes of Health Research (CIHR)
• National Cancer Institute of Canada (NCIC)
• Cystic Fibrosis Foundation Therapeutics (CFFT)
• PrioNet
• Alberta Prion Research Initiative (APRI)

Publications

A detailed listing of Dr. Forman-Kay's publications is available on Pub Med