Simon Sharpe
Associate Professor
BSc, Memorial University of Newfoundland, 1997
PhD, University of Western Ontario, 2002
Postdoc, National Institutes of Health, 2002-2006
| Address | Peter Gilgan Center for Research and Learning 686 Bay St., Room 20.9714 Toronto, ON M5G1X8 |
| Lab | Sharpe Lab |
| Lab Phone | 416-813-7654 ext. 2840 |
| Office Phone | 416-813-7852 |
| ssharpe@sickkids.ca |
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 postdoctoral fellow – using solid state NMR to determine the structures of peptide-antibody complex and integral membrane proteins involved in the pathogenesis of HIV-1. Dr. Sharpe joined the program in Molecular Structure and Function at The Hospital for Sick Children and the Department of Biochemistry in 2006, where his research interests include self-assembling proteins (amyloid formation in degenerative diseases, elastomeric proteins, and others), protein-membrane interactions and integral membrane proteins.
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Research Lab
Research in the Sharpe lab focuses on mechanisms of peptide/protein self-assembly, and the links between sequence, structure, and activity of the resulting macromolecular assemblies. We use a wide range of biophysical tools, which an emphasis on applying solid state and solution NMR spectroscopy to achieve a molecular-level understanding of protein structure and dynamics. For this purpose, the Sharpe lab has dedicated use of 500, 600 and 700 MHz NMR spectrometers fully equipped for biomolecular solution and solid state NMR experiments.
Learn more: Sharpe Lab
Research Description
Molecular-Level Study of Macromolecular Assemblies in Human Health and Disease
The assembly of peptides and proteins into large macromolecular complexes plays an important role in normal biological processes and in the development of many disease states. The primary goal of the research program undertaken in our group is to obtain a molecular-level understanding of several macromolecular assemblies that play important roles in human health and disease. We have used an approach based on solid-state NMR (SSNMR), which has emerged as the technique of choice for investigating the structural and dynamic properties of amyloid fibrils, integral membrane proteins, and other large macromolecular complexes. In addition to providing high-resolution structural data on protein assemblies, this method also permits direct observation of protein-membrane interactions.
To complement the structural information provided by SSNMR, we use a broad range of other biophysical techniques, including solution NMR, transmission electron microscopy (TEM), fluorescence spectroscopy, Fourier-transform infrared spectroscopy (FTIR), and small angle X-ray scattering (SAXS), among others. We are using this multidisciplinary approach to address questions in three key areas: (1) The molecular basis for amyloid assembly and cytotoxicity in model peptides, prions, and in systemic amyloidosis caused by misfolding of apolipoproteins; (2) The assembly and structure of elastomeric proteins – understanding the functional properties of potential biomaterials; and (3) Antagonism of host cell immune response by viral membrane proteins. Our goal in each case is to obtain details of the molecular structure and intermolecular interactions that are important to the biological system. In addition to enhancing fundamental understanding of protein folding, assembly and membrane interactions, our results will provide insight into the mechanisms of human disease, with the ultimate goal of identifying new areas for therapeutic intervention.
Awards & Distinctions
2006-2016 — Canada Research Chair
2010 — Ontario Early Researcher Award
Courses Taught
JBB2026H Protein Structure, Folding and Design
BCH473Y Advanced Research Project in Biochemistry
BCH425H (JBB1425) Structural Biology: Principles and Practice
BCH2024H Applications of Biomolecular Solid-State NMR
Publications
View all publications on PubMed
Direct observation of structure and dynamics during phase separation of an elastomeric protein
Reichheld SE, Muiznieks LD, Keeley FW, Sharpe S
PNAS 2017 114:E4408-E4415 Read
The human amyloid β peptide interactome: binding to somatostatin favors formation of distinct oligomers
Wang H, Muiznieks LD, Ghosh P, Williams D, Solarski W, Fang A, Ruiz-Riquelme A, Pomès R, Watts JC, Chakrabartty A, Wille H, Sharpe S, Schmitt-Ulms G
eLife 2017 6:e28401 Read
Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. Implications for tissue specificity and durability of elastic tissue
Miao M, Reichheld SE, Muiznieks LD, Sitarz EE, Sharpe S, Keeley FW
Biopolymers 2017 107:e23007 Read
Mechanism of amyloidogenesis of a bacterial AAA+ chaperone
Chan SW, Yau J, Ing C, Liu K, Farber P, Won A, Bhandari V, Kara-Yacoubian N, Seraphim TV, Chakrabarti N, Yip CM, Pomes R, Sharpe S and Houry WA
Structure 2016 24:1095-1109 Read
Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses
Bugyei-Twum A, Rakhit R, Galant NJ, Walsh P, Sharpe S, Arslan PE, Westermark P, Higaki JN, Torres R, Tapia J, Chakrabartty A
Scientific Reports 2016 6:25188 Read
The mechanism of membrane disruption by cytotoxic amyloid oligomers formed by prion protein(106-126) is dependent on bilayer composition.
Walsh P, Vanderlee G, Yau J, Campeau J, Sim VL, Yip CM, Sharpe S
J Biol Chem. 2014 289:10419-10430 Read
Conformational transitions of the cross-linking domains of elastin during self-assembly
Reichheld SE, Muiznieks LD, Stahl R, Simonetti K, Sharpe S, Keeley FW
J Biol Chem. 2014 289:10057-10068 Read
Dynamic equilibria between monomeric and oligomeric misfolded states of the mammalian prion protein measured by 19F NMR
Larda ST, Simonetti K, Al-Abdul-Wahid MS, Sharpe S, Prosser RS
J Am Chem Soc. 2013 135:10533-10541 Read
Structures of amyloid fibrils formed by the prion protein derived peptides PrP(244-249) and PrP(245-250)
Yau J, Sharpe S
J Struct Biol. 2012 180:290-302 Read
Structure of an intermediate state in protein folding and aggregation
Neudecker P, Robustelli P, Cavalli A, Walsh P, Lundström P, Zarrine-Afsar A, Sharpe S, Vendruscolo M, Kay LE
Science 2012 336:362-366 Read