Simon Sharpe, PhD
University of Toronto
Department of Biochemistry
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Simon Sharpe obtained his BSc in Cell Biology and Biochemistry at the Memorial University of Newfoundland in 1997. After obtaining a PhD from the biochemistry department of the University of Western Ontario in 2002, he joined Robert Tycko's group at the NIH as a CIHR postdoctoral fellow. Dr. Sharpe joined The Hospital for Sick Children as a scientist in 2006.
- Solid state nuclear magnetic resonance as a tool for structural biology
- Structure and function of membrane proteins
- Protein-lipid interactions
- Protein misfolding and aggregation
My current research focuses on the structural characterization of protein-protein and protein-lipid interactions at biological membranes, using solid state nuclear magnetic resonance (NMR). Solid state NMR has recently emerged as a powerful tool for obtaining high-resolution structural data on biomolecules not accessible to other approaches, such as integral membrane proteins and fibrillar aggregates. Projects in the lab focus on three classes of proteins related to human disease, viral ion channels, pulmonary surfactant proteins and prions, with the goal of determining their structures and investigating their mechanisms of action at cell membranes.
Viral ion channels
Our primary area of investigation is the formation of ion channels by a class of small viral membrane proteins which includes the hepatitis C virus p7 protein, the human respiratory syncytial virus SH protein, the SARS coronavirus E protein and Vpu from HIV-1. These ‘viroporins’ enhance the permeability of host cell membranes, a process which is essential for viral infectivity, making them excellent candidates for development of novel antiviral therapies. However, the structure and functions of viroporins have been poorly characterized. Building from earlier work on the structure of HIV-1 Vpu, we are using solid state NMR to develop structural models for other members of this family, with the goal of understanding the mechanisms of ion channel formation by viroporins. We are also moving towards structural studies of drug-channel interactions.
Role of protein-membrane interactions in prion diseases
The accumulation of misfolded proteins in a fibrillar form is characteristic of several human diseases, including type II diabetes, Alzheimer’s disease and prion diseases (BSE, CJD). It has been proposed that the degenerative nature of these conditions may result from the toxicity of the fibrillar aggregates, though an unknown mechanism. There is growing evidence that the prion protein (PrP) disrupts cell membranes through formation of ion channels, pores, or other protein-lipid complexes, and that this may be a common feature of fibril-forming proteins. We are initiating a project to identify the structures formed by peptides from PrP in the presence of lipid membranes, as a means for determining the basis of their neurotoxicity.
Sharpe S, Yau W-M, Tycko R. (2006) Structure and dynamics of the HIV-1 Vpu transmembrane domain revealed by solid state NMR with magic-angle spinning. Biochemistry 45: 918-933.
Sharpe S, Yau W-M, Tycko R. (2005) Expression and purification of a peptide from the Alzheimer’s Beta-amyloid protein for solid-state NMR. Protein Express. Purif. 42: 200-210.
Goodyear DJ, Sharpe S, Grant CWM, Morrow MR. (2005) Molecular dynamics simulation of transmembrane polypeptide orientational fluctuations. Biophysical Journal 88:105-117.
Sharpe S, Kessler N, Anglister JA, Yau W-M, Tycko R. (2004) Solid-state NMR yields structural constraints on the V3 loop from HIV-1 gp120 bound to the 447-52D antibody Fv fragment. J. Am. Chem. Soc. 126: 4979-4990.
Sharpe S, Barber KR, Grant CWM, Goodyear D, Morrow MR. (2002) Organization of model helical peptides in lipid bilayers: Insight into the behaviour of single-span protein transmembrane domains. Biophysical Journal 83: 345-358.
Sharpe S, Barber KR, Grant CWM. (2002) Interaction between ErbB-1 and ErbB-2 transmembrane domains in bilayer membranes. FEBS Letters 519: 103-107.
Sharpe S, Barber KR, Grant CWM. (2002) Evidence of a tendency to self-association of the transmembrane domain of ErbB-2 in fluid phospholipid bilayers. Biochemistry 41: 2341-2352.
Sharpe S, Grant CWM, Barber KR, Giusti J, Morrow MR. (2001) Structural implications of a Val-Glu mutation in transmembrane peptides from the EGF receptor. Biophysical Journal 81: 3231 3239.
Sharpe S, Grant CWM. (2000) A transmembrane peptide from the human EGF receptor: Behaviour of the cytoplasmic juxtamembrane domain in lipid bilayers. Biochim. Biophys. Acta. (Biomembranes) 1468: 262-272.
Sharpe S, Barber KR, Grant CWM. (2000) Val659Glu mutation within the transmembrane domain of ErbB-2: Effects measured by 2H NMR in fluid phospholipid bilayers. Biochemistry 39: 6572-6580.