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
Email 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 now includes structure/dynamics studies of self-assembling proteins (eg. amyloid formation in degenerative diseases, elastomeric proteins, and others), protein-membrane interactions, and biological phase separation.

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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 combining atomistic details of protein structure and dynamics from NMR spectroscopy with molecular level data obtained from X-ray scattering, fluorescence microscopy, electron microscopy, and other approaches.  For this purpose, the Sharpe lab has dedicated use of 600 and 700 MHz NMR spectrometers equipped for biomolecular solution and solid state NMR experiments, and access to the suites of biophysical instruments available at SickKids (SBC Facility, Imaging Facility, NBIF).

Current Lab Members:

Dr. Sean Reichheld – Research Associate (structure and dynamics of human tropoelastin; NMR; protein biophysics)

James Otis – PhD Student (sequence determinants of structure, dynamics, assembly and material properties of resilin)

Asal Nady – PhD student (structural studies of lipid binding and amyloid formation by human serum amyloid A)

Robert Lu – PhD student (role of glycosaminoglycans in phase separation and assembly of tropoelastin)

Eson Lau – MSc student (structure of human matrix gla protein, an inhibitor of elastin calcification)

 

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 an atomistic and molecular-level understanding of several macromolecular assemblies that play important roles in human health and disease.

(1) Tropoelastin is the monomeric precursor to elastin, the primary elastic component in lung alveoli, arteries, bladder and uterus. This essential protein assembles in the extracellular matrix (ECM) through a complex set of intermolecular interactions including self-assembly through phase separation, binding to ECM proteins, and enzymatic crosslinking to form a polymer – defects in which lead to cardiovascular disease.  We are working to understand the assembly process at the atomic level and to link mutations with human disease.

(2) Resilin is a polymeric elastic protein that is critical for the biology of insects and has unusual mechanical properties that make it a useful precursor for developing biomaterials.  Using approaches we previously developed for elastin, we are developing an atomistic understanding of the resilin assembly pathway and the connections between sequence-assembly-function.

(3) Serum amyloid A is an apolipoprotein expressed as part of the acute-phase inflammatory response. Normally associated with modified activity of high-density lipoprotein (HDL) during inflammation, in patients with chronic inflammatory illnesses SAA misfolds into amyloid fibrils, causing systemic amyloidosis and increasing morbidity/mortality. We have defined the structure and lipid binding mechanism for SAA, and are now studying the molecular basis by which different triggers induce AA amyloidosis.

Publications

View all publications on PubMed

Structural studies of a serum amyloid A octamer that is primed to scaffold lipid nanodiscs
Nady A, Reichheld SE, Sharpe S
Protein Science 2024 33:e4983  Read

A secreted bacterial protein protects bacteria from cationic antimicrobial peptides by entrapment in phase separated droplets
Ostan NKH, Cole GB, Wang FZ, Reichheld SE, Moore G, Pan C, Yu R, Lai CCL, Sharpe S, Lee HO, Schryvers AB, Moraes TF
PNAS Nexus 2024 3:139

Directed assembly of elastic fibers via coacervate droplet deposition on electrospun templates
Lau K, Reichheld SE, Xian M, Sharpe S*, Cerruti M*
Biomacromolecules 2024 25:3519-3531

Sequence context and complex Hofmeister salt interactions dictate phase separation propensity of resilin-like polypeptides
Otis JB, Sharpe S
Biomacromolecules 2022 23:5225-5238

Directed assembly of elastic fibers via coacervate droplet deposition on electrospun templates
Lau K, Reichheld SE, Sharpe S*, Cerruti M*
RSC Soft Matter 2022 18:3257-3266

The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin
Reichheld SE, Muiznieks LD, Huynh Q, Wang N, Ing C, Miao M, Sitarz EE, Pomes R, Sharpe S*, Keeley FW*
Biopolymers 2021 112:e23414

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

FRET analysis of the promiscuous yet specific interactions of the HIV-1 Vpu transmembrane domain
Cole GB, Reichheld, SE, Sharpe S
Biophysical Journal 2017 https://doi.org/10.1016/j.bpj.2017.09.010

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

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