Simon Sharpe

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

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.

Protein phase-separation and elastic biomaterial formation
ELP assembly model


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