Jeffrey Lee

Dr. Lee is the Undergraduate Coordinator for the Specialist Program in Pathobiology, and Associate Chair, Life Science Education in LMP. He also runs LMP's Summer Undergraduate Research Experience Program (SURE).

He completed his graduate studies with Dr. P. Lynne Howell at the University of Toronto/Hospital for Sick Children and followed that with a post-doctoral fellowship with Dr. Erica Ollmann Saphire at The Scripps Research Institute in La Jolla, CA. Jeff returned to the University of Toronto to start his own lab in July 2010.

His research focuses on understanding the mechanisms of viral-cell and cell-cell fusion. 

Research Synopsis

If membranes were able to fuse spontaneously, chaos would result. The merger of trillions of vesicles, organelles, and cells would eliminate compartmentalization, cellularity, and life itself. Fortunately, the energy barriers related to membrane deformation and fusion are high, thus two membranes cannot spontaneously merge. Membrane fusion is a key process in viral entry and reproductive biology. 

Our laboratory strives to understand the molecular mechanisms that viral and cellular fusogens use to modulate multiple biological processes, such as viral-host entry and sperm-egg fusion. The overarching vision is focused on identifying and better understanding the role of membrane fusogens at the atomic level. Our primary research objectives are focused on two main areas:

1. Understand the complete molecular mechanisms and multiple functions of viral fusogens
2. Understand the diversity of cell-cell fusogens across the kingdoms of life

Viral fusogens

The entry of many major human viral pathogens, such as influenza A virus, HIV-1, Ebola virus, HTLV-1, Marburg virus, Coronavirus, Lassa virus, among others, into host cells is mediated via carbohydrate-rich viral surface glycoproteins (GPs).

The GP is often the only virus encoded protein on the virus particle surface, and facilitates attachment, tropism, and host-viral membrane fusion.

Since 2010, my group has extensively studied viral GPs and their function in membrane fusion (Cook et al 2022 Communications Biology; Dean et al 2022 mBio; Serrao et al 2021 Cell Reports; Cook et al 2017 PNAS; Cook et al 2015 JBC; Aydin et al 2014 J Virol; Aydin et al 2014 Protein Sci; Aydin et al 2013 FASEB J). 

Cell-cell fusion

The fusion of membranes is also important in many cellular processes, such as fertilization (sperm-egg fusion), placenta development (trophoblast fusion), skeletal muscle development (myoblast fusion), bone development (osteoclast fusion), among other processes.

The mechanisms of cell-cell fusion are poorly defined and have generally been based on the mechanisms employed by viruses for fusion. Recently, it seems some cell-cell fusion processes may be evolutionarily related to the viral glycoproteins (for example C. elegans EFF-1 protein, and syncytin-1/syncytin-2 in placenta development). We are interested in understanding the various mechanism of cell-cell fusion and how it relates to virus-cell fusion.

In my lab, we begin each project by determining the three-dimensional structure of a key cellular protein, immune molecule, or viral protein complex, and then use the structure to drive the focus of subsequent functional analysis.

We integrate diverse techniques from crystalline, cryo-EM and solution scattering, molecular biology, protein biochemistry, virology, cell biology, and immunology to deliver a holistic picture that will define new paradigms and fundamental principles in biology. 

Training opportunities are currently available for prospective graduate students through the Department of Laboratory Medicine and Pathobiology. Prospective students are encouraged to contact the PI directly (jeff.lee@utoronto.ca).

Selected Publications

TDR Vance, P Yip, E Jiménez, S Li, D Gawol, J Byrnes, I Usón, A Ziyyat, and JE Lee. (2022). SPACA6 ectodomain structure reveals a conserved superfamily of gamete-fusion associated proteins. Communications Biology. 5(1):984.  

JD Cook, A Khondker, and JE Lee. (2022). Conformational plasticity of the HIV-1 gp41 immunodominant region is recognized by multiple non-neutralizing antibodies. Communications Biology. 5(1):291. 

TT Dean, VHB Serrao, and JE Lee. (2022). Structure of the core postfusion porcine endogenous retrovirus fusion protein. mBio. 13(1):e0292021

VHB Serrao, JD Cook and JE Lee. (2021). Snapshot of an influenza virus glycoprotein fusion intermediate. Cell Reports. 35(7):109152

VHB Serrao and JE Lee. (2020). FRETing over SARS-CoV-2: conformational dynamics of the spike glycoprotein. Cell Host Microbe. 28(6):778-79.

J Mercer, JE Lee, EO Saphire and SA Freeman. (2020). Snapshot: Enveloped virus entry. Cell. 182(3):786.

TDR Vance and JE Lee. (2020). Virus and eukaryote fusogen superfamily. Current Biology. 30(13):R750-54.

FC Azimi and JE Lee. (2019). Structural perspectives on HIV-1 Vif and APOBEC3 restriction factor interactions. Protein Sci. 29(2):391-406.

D Tarade, JE Lee and M Ohh. (2019). Evolution of metazoan oxygen-sensing involved a conserved divergence of VHL affinity for HIF1α and HIF2α. Nat Commun. 10(1):3293.

Y Kano, T Gebregiworgis, CB Marshall, N Radulovich, BPK Poon, J St-Germain, JD Cook, I Valencia-Sama, BMM Grant, SG Herrera, J Miao, B Raught, MS Irwin, JE Lee, JJ Yeh, ZY Zhang, MS Tsao, M Ikura, M Ohh. (2019). Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation. Nat Commun. 10(1):224.

D Tarade, CM Robinson, JE Lee, M Ohh. (2018) HIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease. Nat Commun. 9(1):3359.

JD Cook, A Sultana, and JE Lee. (2017). Structure of the infectious salmon anemia virus receptor complex illustrates a unique binding strategy for attachment. Proc Natl Acad Sci U S A. 114(14): E2929-2936.

H Aydin, A Sultana, S Li, A Thavalingam, and JE Lee. (2016). Molecular architecture of the human sperm izumo1 and egg Juno fertilization complex. Nature. 534(7608):562-5.

T Hashiguchi, ML Fusco, ZA Bornholdt, JE Lee, AI Flyak, R Matsuoka, D Kohda, Y Yanagi, M Hammel, JE Crowe Jr, and EO Saphire. (2015). Structural basis of Marburg virus neutralization by a cross-reactive human antibody. Cell. 160(5):904-12.

KK Siu, A Sultana, FC Azimi and JE Lee. (2013). Structural determinants of HIV-1 Vif susceptibility and DNA binding in APOBEC3F. Nature Communications. 4 (4), 2593.

H Aydin, JD Cook and JE Lee. (2013). Crystal structures of beta- and gamma-retroviral fusion proteins reveal a role for electrostatic stapling in viral entry. Journal of Virology. 88 (1)143-53.

H Aydin, BM Smrke and JE Lee. (2013). Structure of a retroviral fusion protein from a virus that undergoes a two-step viral entry mechanism. FASEB Journal. 27 5072-82.

JD Cook and JE Lee. (2013). The secret life of viral entry glycoproteins: moonlighting in immune evasion. PLoS Pathogens. 9 (5) e1003258. 1-5.

Honours and Awards

LMP Sustained Excellence in Education Award, University of Toronto (2022)

LMP Award for Excellence in Graduate Education, University of Toronto (2015, 2021)

Canada Research Chair

2015 Merck Irving S. Sigal Award (American Society of Microbiology)

CIHR New Investigator Award

2010 Spicer Young Investigator Award (Stanford University/Stanford Synchrotron Radiation Lightsource)