James J. Cheetham
|Degrees:||B.Sc. (McMaster University), Ph.D. (McMaster University)|
|Phone:||613-520-2600 x 3867|
|Office:||Office: 4615 CTTC Building|
Protein-lipid interactions lie at the heart of many biological processes including signal transduction, exocytosis and neurotransmitter release. In particular protein-lipid interactions are important in the regulation of the synaptic vesicle cycle.
Neurons communicate through the release of neurotransmitters from synaptic vesicles by exocytosis. Defects in this process may result in neuronal disorders such as schizophrenia, epilepsy, and depression. To avoid failures in neurotransmitter release, rapid replenishment of synaptic vesicles must occur. The synapsins comprise a family of synaptic vesicle-associated proteins that are important for sustaining neurotransmitter release at high frequencies of stimulation. Synapsin I binds to both synaptic vesicles and the cytoskeleton and clusters vesicles at presynaptic nerve terminals where it regulates the availability of vesicles for exocytosis and neurotransmitter release.
Our research has shown that synapsins stabilize synaptic vesicles. We also found that the binding of the synaptic vesicle protein, synapsin I is modulated by the lipid packing within membranes. Cells can control the lipid packing in their membranes by metabolically altering the lipid composition. We use liposomes, monomolecular films and atomic force microscopy, to investigate the effects of phospholipid composition and packing on protein binding. Through such studies, we are obtaining a better understanding of the physicochemical parameters that affect the interaction of proteins with membranes. We use a variety of modern approaches that bridge biophysics, biochemistry, molecular biology and bioinformatics. Included are cloning and expression technologies that involve site-directed mutagenesis and recombinant protein purification and characterization as well as model membrane production and characterization. Biophysical techniques which are employed in our research include fluorescence spectroscopy, liposome production, isothermal titration calorimetry (ITC), atomic force microscopy (AFM), near-field microscopy and various types of chromatography.
Computational Biology and Simulation
Presynaptic nerve terminals are located at the ends of nerve cells; a signal propagating through a nerve cell reaches one of these compartments before being transmitted to an adjacent nerve cell. A tethered particle system (TPS) is a type of impulse-based model recently developed for the simulation of deformable biological structures. In a TPS, collisions can cause approaching particles to rebound outwards, as one would expect, but they can also caused separating particles to retract inwards. We are using a TPS model to simulate a presynaptic nerve terminal. The model captures the clustering of synaptic vesicles in the presence of synapsin I. The simulated presynaptic nerve terminal is being used, to predict how a changes in various parameters affects the size of vesicle clusters, and reliability of neurotransmitter release.
Al-aubidy, B., , Dias,A., Bain, R., Jafer, S., Dumontier, M., Wainer,G., and Cheetham, J. (2007) Advanced DEVS models with applications to biology and medicine. AIS 2007, Artificial Intelligence, Simulation and Planning. Buenos Aires, Argentina. .
Pitre S, Dehne F, Chan A, Cheetham J, Duong A, Emili A, Gebbia M, Greenblatt J, Jessulat M, Krogan N, Luo X, Golshani A. , (2006) PIPE: a protein-protein interaction prediction engine based on the re-occurring short polypeptide sequences between known interacting protein pairs, BMC Bioinformatics, 7, 365.
Murray, J., Cuccia, L., Ianoul, A., Cheetham, J.J. and Johnston, L.J. (2004) Imaging the Selective Binding of Synapsin to Anionic Membrane Domains, ChemBioChem, 5, 1-7.
Hurley, S.L., Brown, D.L. and Cheetham, J.J. (2004) Cytoskeletal Interactions of Synapsin I in Non-Neuronal Cells, Biochem. Biophys. Res. Comm., 317, 16-23.
Cheetham, J.J., Murray, J., Ruhkalova, M., Cuccia, L., McAloney, R., Ingold, K.U. and Johnston, L.J. (2003) Interaction of synapsin I with membranes, Biochem. Biophys. Res. Comm., 309, 823 -829.
Cheetham, J.J., Dehne, F., Rau-Chaplin, A., Stege, U. and Taillon, P.J. (2003) Solving Large FPT Problems on Course Grained Parallel Machines, Journal of Computer and System Sciences, 67, 691-706.
Cheetham, J.J., Weber T., Hilfiker-Rothenfluh, S., Benfenati, F., Brunner, J., Czernik, A.J. and Greengard, P. (2001) Identification of Domain C Peptide Sequences of Synapsin I that Insert into Lipid Membranes, Biochemical J., 354, 5