Research Highlights

17 Sept 2014

McQuibban and McNeill labs reveal a novel signaling pathway in latest issue of Cell

Planar cell polarity (PCP), is a form of tissue organization that is critical for normal development. Dysfunction in PCP can result in several human cancers. PCP can be readily assessed in the Drosophila eye, by the ordered ommatidial array shown below:

One of the key factors in the PCP pathway is the cell adhesion molecule called Fat. Using a combination of genetics and biochemistry, the McNeill (Mt. Sinai, Dept. Mol. Gen.) and McQuibban labs have discovered that Fat undergoes a proteolytic cleavage that releases a soluble cytoplasmic fragment. This cleavage unmasks an embedded mitochondrial targeting motif and results in Fat import into mitochondria. Once inside mitochondria, Fat regulates changes in intracellular metabolism. This is the first example of a cell surface protein being relocated to mitochondria to orchestrate an important signaling pathway

Read more about Angus' research on the McQuibban Lab website

9 May 2014

Alex Palazzo on Junk DNA

Dr. Palazzo in collaboration with T. Ryan Gregory from the University of Guelph published a perspective on “The Case for Junk DNA” that appeared in the May issue of PLoS Genetics and is highlighted in on the National Geographic website.

To read more about Alex's work, visit his lab website at:

http://biochemistry.utoronto.ca/palazzo/index.htm

12 October 2012

Trevor Moraes awarded Tier 2 Canada Research Chair

Research in the Moraes lab examines protein and ion translocation across bacterial membranes. In particular, Dr. Moraes dissects the components of these pathways examining their interactions in molecular detail. Biochemical tools such as X-ray crystallography provide atomic resolution 3D-models of the proteins, while surface plasmon resonance, isothermal calorimetry or bio-layer interferometry are used to determine kinetic parameters and validate models that describe the mechanism of action. These membrane proteins function together as a complexes to facilitate efficient transport that is essential for pathogenic bacteria to survive within the host, thus this research provides the basis for developing novel antimicrobial therapeutics.

Please visit Trevor's website for more information

20 September 2012

Chair Reinhart Reithmeier Elected Fellow of the Canadian Academy of Health Sciences

At a ceremony held in Ottawa on September 20, 2012, Biochemistry Chair Reinhart Reithmeier was admitted as a Fellow to the Canadian Academy of Health Sciences (CAHS) “having demonstrated both distinctive accomplishments and the commitment to advance health sciences”.  

A major goal of the CAHS is to provide timely, informed, science-based and unbiased assessments of urgent issues affecting the health of Canadians.  Reinhart, well-known internationally for his work on membrane proteins and human disease, has also been relentless in promoting the importance of basic research and the need for increases in funding to support excellence and to remain competitive.

CAHS President Thomas Marrie presents Reinhart Reithmeier with certificate of membership as a Fellow of the Canadian Academy of Health Sciences (CAHS) 

09 December 2011

Special issue of the Journal of Biomolecular NMR on the occasion of Lewis Kay’s 50th birthday

In the Editorial introducing this special issue [J Biomol NMR (2011) vol 51], Kevin Gardner, Anthony Mittermeier and Frans Mulder note that Lewis is being honoured for his "innovative contributions to biomolecular NMR spectroscopy, as well as for his role as inspirer for a large group of young research professionals."

They further comment that "Lewis has consistently been a pioneer in the development of novel methods essential to increasing the size of proteins that may be studied by NMR....His lab forged ahead with clever biochemical tricks for incorpo- rating protonated methyl groups in otherwise deuterated proteins, and developed methyl TROSY experiments that permit well-resolved spectra to be obtained for high molecular weight complexes, extending to 1 MDa."

"In addition, the Kay lab has extensively developed and applied new methodologies for studying low-populated states of proteins and their roles in biology. Building on transverse relaxation dispersion experiments, the Kay lab has introduced approaches to elucidate the three-dimensional structures and dynamics of protein states so weakly populated that they are ‘‘invisible’’ to standard NMR experiments and most other biophysical and structural techniques."

03 May 2011

Daniela Rotin wins "Women of Action" Award

Daniela Rotin was honoured by the Israel Cancer Research Fund (IRCF) as a recipient of the prestigious "Women of Action" award at a gala event held at the Sheraton Hotel in Toronto on May 3, 2011.

Founded in 1975, IRCF is one of the largest private sources of funding for cancer research in Israel and has helped to support the early work of scientists such as 2004 Nobel laureates Aaron Ciechanover and Avram Hershko, discoverers of the ubiquitin proteostasis system. For many years Daniela has served on the ICRF scientific review panel that selects research grant award winners through a rigorous peer-review system. Close to 2,000 grants totalling over $40M have been awarded with funds raised by ICRF at events like the gala held in Toronto.

Congratulations to Daniela for this important recognition.

29 April 2011

David Isenman's Science article resolves a long-standing controvery in the complement field

In a study published in the April 29th issue of Science, Professor David Isenman of Biochemistry and Jean van den Elsen of the University of Bath shed light on the complex between complement receptor 2 and its ligand C3d, both of which are constituents of an innate immune system of our body known as complement.

The molecular details of the CR2-C3d interface have been mired in controversy for the past decade. Specifically, in 2001 an X-ray crystal structure of the complex consisting of C3d and the first two domains of CR2 was published in Science. However, from the start, that structure was discordant with much biochemical data in the literature, and over the years the discrepancies have only increased.

The detailed knowledge of the receptor-ligand interface provided by the new structure of this complex has implications as both a potential therapeutic target, in the case of antibody-mediated autoimmune diseases, and as something that may be exploited in enhancing the efficacy of vaccines.

“We recognize that the goal of applying this knowledge to autoimmune therapies and enhanced vaccine efficiency will not be trivial. But the structural scaffold for further discoveries is now in place,” said Isenman.

Click here to read the full article in News @ the University of Toronto.

01 September 2010

Harry Schachter Honoured with the Rosalind Kornfeld Award

The Society for Glycobiology has just announced that Dr. Harry Schachter (Professor Emeritus of Biochemistry, University of Toronto; Senior Scientist Emeritus, Research Institute, Hospital for Sick Children, Toronto) has been awarded the Rosalind Kornfeld Award for Lifetime Achievement in Glycobiology.

Dr. Schachter made many seminal contributions to glycobiology and the biochemistry of glycan synthesis for more than four decades. Early on Dr. Schachter was a leader in establishing many robust enzyme assays to characterize Golgi glycosyl transfersase activities in both the N- and O-glycosylation pathways. He defined complex enzyme acceptor specificities and revealed the order in the N-glycan branching pathway leading to complex N-glycans on cell surface receptors and secreted proteins. His group purified GlcNAc-transferases I and II from biological sources, cloned and expressed the respective genes, and then he turned his attention to their functions in development and disease. He collaborated with Dr. Jamie Marth to generate mice with germ line deletions. Dr. Schachter’s group then generated similar mutants in C. elegans, which has three GlcNAc-transferase I genes. They made the triple mutant and learned much about N-glycan synthesis in the worm by characterizing the affected glycans and glycoproteins by mass spectrometry with Dr. Vern Reinhold.

Dr. Schachter’s enthusiasm, integrity and forthright style are widely recognized and appreciated, and have made him an outstanding collaborator, an excellent communicator of science, and a model for young scientists. He collaborated with Dr Pamela Stanley on one of the first glycosylation mutants of cultured cells to reveal that Lec1 CHO cells lack GlcNAcT-I activity. He worked with Dr. Jaak Jaeken to characterize the first Carbohydrate-Deficient Glycoprotein Syndrome (CDG-IIa; now known as Congenital Disorders of Glycosylation) and developed a mouse model of CGD-IIa with Dr. Jamie Marth. Most recently, Dr. Schachter has explored the biological functions of N-glycans in Drosophila development with Dr Gabrielle Boulianne. This study indicates that GlcNAcT-I expression in the brain of Drosophila has a tissue-specific role in the regulation of insulin signaling and life span. Many others, both collaborators and competitors, have benefited from Dr. Schachter’s wide knowledge, encouragement and advice. He has authored more than 160 original papers and 80 scholarly reviews, and edited several books.

Dr. Schachter has also served the scientific community in a number of ways. He was an Associate Editor for the Journal of Biological Chemistry and Chief Editor of Glycoconjugate Journal, Convenor and Chair of the 11th International Symposium on Glycoconjugates and the 2nd International Symposium on Glycosyl transferases. He has been a strong supporter of glycobiology through his teaching, mentoring of students and research lectures at international meetings. In recognition of his seminal and numerous scientific contributions to glycobiology in development and disease, and his leadership in promoting the field of glycobiology, the Society for Glycobiology has awarded Dr. Schachter the 2010 Rosalind Kornfeld Award.

01 June 2010

Shana Kelley wins Steacie Prize

NSERC announced today that Professor Shana Kelley is one of six 2010 NSERC E.W.R. Steacie Memorial Fellowship recipients. Each fellow receives a research grant of $250,000 and the university normally receives a contribution to the fellow's salary to provide teaching and administrative relief. Shana will use the funding to further her studies on the development of chip-based sensors.

From the NSERC press release...
Shana is intent on developing low-cost diagnostic technologies to be used in developing countries. She has developed a chip-based sensor (see September 28, 2009 listing) that can detect trace quantities of DNA, RNA and protein analytes in samples, and that has already been applied for early diagnosis of cancer. Shana is further developing this technology for tuberculosis detection. This involves the development of new nanomaterials that will enable sensitive sensors to detect minuscule traces of the deadly tuberculosis pathogen. The current tools used for diagnosis in the parts of the world most affected by tuberculosis and similar diseases require relatively large samples and are too slow to provide the level of control needed to reign in the spread of infection.

25 May 2010

Lewis Kay elected to the Royal Society

We were delighted to learn that Lewis Kay has been elected to the Royal Society (UK) for his work on NMR spectroscopy. He and his group have developed many of the recent technical advances that have pushed the size limit of protein complexes that can be examined by NMR spectroscopy beyond 500 kDa. For example, methyl-TROSY was used to elucidate the structure and aspects of the dynamics of the 670 kDa 20S proteasome core particle. He has also developed methods for studying invisible excited states of proteins by NMR and is applying them to furthering our understanding of protein folding and conformational dynamics.

Lewis is only the 5th member in the over 100 year history of the Department to receive this very prestigious honour. Other FRS (UK) are our first Chair, Archibald Byron Macallum, Charles Hanes, Gordon Dixon and David MacLennan.

Congratulations to Lewis!

18 December 2009

Igor Stagljar and co-workers discover new regulator of the EGF receptor

Reprinted from NEWS @ U of T, by Chris Garbutt

Researchers at the University of Toronto and Goethe University in Germany have discovered a protein that can inhibit the growth of cancer cells, providing crucial clues for the future development of new drugs to treat the disease.

The protein, called HDAC6, controls the stability of the epidermal growth factor receptor (EGFR), a key player in cancer.

"Our teams discovered that HDAC6 acts as a molecular brake to shut down the expression of the human EGFR," said Professor Igor Stagljar of biochemistry and molecular genetics, one of the lead authors of a study published in the Dec. 22 issue of the journal Science Signaling. Professor Ivan Dikic at Goethe University was co-lead on the study.

"Since EGFR is overactive in breast, lung, colon and pancreatic cancers, this discovery can open new avenues for cancer treatment," said Stagljar, a principal investigator at U of T's Terrence Donnelly Centre for Cellular and Biomolecular Research.

EGFR is nestled into the cell membrane on the surface of human cells where, after it gets activated by molecules called ligands, causes cells to divide. In several cancer cell types, the activity of this receptor is dramatically increased, which stimulates cells to grow rapidly and out of control. Because of its key role in driving the proliferation of cells, EGFR is a target of several cancer drugs currently in development, as well as several approved therapies.

To study the cellular role of EGFR in human cells, Stagljar's lab first developed a technology called MYTH, a unique test that can monitor interactions between membrane proteins. This technology can reveal proteins that tightly associate with EGFR on the cell surface. Using MYTH, the researchers identified more than 80 proteins that interact, and presumably communicate, with the human EGFR. Among them was a cytosolic protein, HDAC6, which they showed helps in stabilizing EGFR in human cells.

"These findings offer fresh insight into how HDAC6 regulates EGFR degradation and provides clues for the design of improved cancer therapies," Stagljar said. Specifically, a carefully planned combinatorial chemotherapy that inhibits both the EGFR receptor and its newly identified "brake" (HDAC6) could have a beneficial effect for treating breast, lung, colon, and pancreatic cancers.

In the next phase of their research, Stagljar and his colleagues plan to extend the MYTH technology to interrogate all human receptors that regulate cell proliferation and are therefore implicated in the onset of cancer. Such a global analysis of proteins that associate with human cell surface receptors may provide novel avenues for the treatment of different types of cancers.

28 September 2009

Shana Kelley and co-workers create microchip that can detect type and severity of cancer

Reprinted from NEWS @ U of T, by Elaine Smith

As reported Sept. 27 in Nature Nanotechnology, the research groups of Shana Kelly and Ted Sargent have used nanomaterials to develop an inexpensive microchip sensitive enough to quickly determine the type and severity of a patient's cancer so that the disease can be detected earlier for more effective treatment. Their new device can easily sense the signature biomarkers that indicate the presence of cancer at the cellular level, even though these biomolecules - genes that indicate aggressive or benign forms of the disease and differentiate subtypes of the cancer - are generally present only at low levels in biological samples. Analysis can be completed in 30 minutes, a vast improvement over the existing diagnostic procedures that generally take days.

"Today, it takes a room filled with computers to evaluate a clinically relevant sample of cancer biomarkers and the results aren't quickly available," said Shana Kelley, a professor in the Leslie Dan Faculty of Pharmacy and the Faculty of Medicine, who was a lead investigator on the project and a co-author on the publication. "Our team was able to measure biomolecules on an electronic chip the size of your fingertip and analyse the sample within half an hour. The instrumentation required for this analysis can be contained within a unit the size of a BlackBerry." Conventional, flat metal electrical sensors were inadequate to sense cancer's particular biomarkers. Instead, they designed and fabricated a chip and decorated it with nanometre-sized wires and molecular "bait." "Uniting DNA - the molecule of life - with speedy, miniaturized electronic chips is an example of cross-disciplinary convergence," said Sargent. "By working with outstanding researchers in nanomaterials, pharmaceutical sciences, and electrical engineering, we were able to demonstrate that controlled integration of nanomaterials provides a major advantage in disease detection and analysis."

"We rely on the measurement of biomarkers to detect cancer and to know if treatments are working," said Dr. Tom Hudson, president and scientific director of the Ontario Institute for Cancer Research. "The discovery by Dr. Kelley and her team offers the possibility of a faster, more cost-effective technology that could be used anywhere, speeding up diagnosis and helping to deliver a more targeted treatment to the patient." The team's microchip platform has been tested on prostate cancer, as described in a paper published in ACS Nano, and head and neck cancer models. It could potentially be used to diagnose and assess other cancers, as well as infectious diseases such as HIV, MRSA and H1N1 flu.

01 May 2009

Shana Kelley is Named Top 40 under 40

Dr .Shana Kelley, Professor of Biochemistry at the University of Toronto and Director, Division of Biomolecular Sciences, Faculty of Pharmacy, has been named to this year's Top 40 Under 40.

Canada's Top 40 Under 40 is a prestigious national program founded and managed by the Caldwell Partners to celebrate leaders of today and tomorrow and to honour Canadians below the age of 40 who have achieved a significant level of success. The program is designed to promote mentorship and professional development by introducing these leaders to the established business community and by promoting them as role models for young Canadians. In choosing the recipients, the board at Caldwell Partners considers the nominees' vision and leadership; innovation and achievement; impact; community involvement and contribution; and growth/development strategy.

In an interview with News @University of Toronto, Shana said that this recognition is especially meaningful to her. "I think it's quite important that those of us who pursue careers in academics make sure that we maximize the tangible positive impact we make -- whether it be through our research or teaching or whatever we pursue as faculty," said Kelley. "This award recognizes impact and thus I think it encourages us to be all we can be."

Shana Kelley

May 2009

Charles Deber Wins American Peptide Society Goodman Award

Dr. Charles M. Deber, Professor of Biochemistry at the University of Toronto and Acting Head of the Division of Molecular Structure and Function at the Research Institute, Hospital for Sick Children, is the first recipient of the Goodman Award of the American Peptide Society.

Charles is known worldwide for his seminal research on the structure and function of membrane peptides and proteins, and in the examination of disease states that involve misfolding of membrane proteins. At the more fundamental level he was among the first to recognize that peptide and protein folding in membranes had fundamental differences from peptide and protein folding in aqueous environments. This led to a critical re-evaluation of the structural properties in amino acids in proteins that are in membrane environments, which has provided new tools for the design of membrane peptides and proteins. Among these tools, the web based TM Finder Program is a most valuable tool, available worldwide.

As a mentor and teacher, Dr. Deber’s contributions also have been exemplary. He teaches widely acclaimed courses from large undergraduate courses, to advanced Chemistry courses for graduate students. For his excellent undergraduate teaching he received the W.T. Aikins Award from the University of Toronto. He has mentored more than 60 graduate students and postdoctoral fellows, many of who have gone on to have outstanding careers in academia and industry. Finally, Charles has made many outstanding contributions in service to the peptide field
worldwide. In addition to being President of the American Peptide Society from 1991-1993, he has been a long time Editor of Peptide Science, on the editorial board of several international journals in the field, and has organized or
helped organize several international conferences.

The Murray Goodman Scientific Excellence and Mentorship Award is
well-deserved recognition for the above and many other contributions.

Charles Deber

29 May 2008

Ken Lau and Jim Dennis discover how cell surface receptor levels are regulated by nutrient availability and by the number of receptor N-glycans

Ken Lau won the Beckman-Coulter Prize for the best graduate student paper of 2007, and gave a lecture on May 29th at the International Symposium Celebrating the 100 Anniversary of the Department of Biochemistry at U. of T.

The Lau et al paper published in Cell (2007) 129:123 entitled "Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation" provides new insight on the role of protein N-glycosylation in the adaptation of the cell surface with changes in metabolism.

Their work demonstrates that the number of N-glycans per polypeptide cooperates with physical properties of the Golgi pathway to regulate surface levels of receptors and transporters. Using computational modeling and experimental examples in T cell and epithelial cells, they show that galectins, a family of mammalian lectins binds to N-glycan on membrane glycoproteins. This multivalent interaction enhances surface residency dependent on the number of N-glycans and their GlcNAc-branching. In turn branching increases with the availability of the donor substrate UDP-GlcNAc. UDP-GlcNAc biosynthesis utilizes key metabolites in carbon, nitrogen and energy homeostasis (fructose-6P, glutamine, acetyl-CoA and UTP). Glycoproteins with high numbers of N-glycans (e.g. EGFR, IGFR, FGFR, PDGFR) tend to be bound to galectins, and exhibit early and graded increase in cell surface expression in responses to increasing UDP-GlcNAc concentration, while glycoproteins with few N-glycans (e.g. TbR, CTLA-4, GLUT4) exhibit delayed and switch-like responses. These results suggest a mechanism for metabolic regulation of cellular transition between growth and arrest arising from apparent co-evolution of N-glycan number and biosynthesis. Animal models of reduced N-glycan branching suggest that this network regulates T cell activation and autoimmunity, tumor progression, glucose metabolism, and stem cell maintenance and aging.

Ken completed his PhD in the Dennis lab and is currently doing postdoctoral work in Dr. Lauffenbergers group at Harvard.

Ken Lau (holding certificate) is joined by (left to right) his supervisor Jim Dennis, Harry Schachter, who provided advice and support throughout the project, and Graduate Coordinator, Jim Rini.

February 2008

Stagljar lab discovers novel approach to identify pathogen inhibitors

Microbial resistance to antibiotics is a serious and growing threat to human health. Arnoldo et al. used a novel approach that combines chemical and genetic perturbation of bakers yeast to find new targets that might be effective in controlling infections caused by the opportunistic human pathogen Pseudomonas aeruginosa. P. aeruginosa is the primary cause of mortality with cystic fibrosis patients and has demonstrated an alarming ability to resist antibiotics.
In this study, Arnoldo et al. identified the first small molecule inhibitors of ExoS, a toxin playing a pivotal role during P. aeruginosa infections. One of these compounds, exosin, likely works by modulating the toxin’s enzymatic activity. The authors further show that this inhibitor protects mammalian cells against P. aeruginosa infection. Finally, they used yeast functional genomics tools to identify several yeast homologues of the known human ExoS targets as possible targets for the toxin.

This innovative approach is an important advance, not only for the value it may have in cystic fibrosis treatment, but also because this technique could be used to design novel therapies for any bacterial pathogen as well as the HIV virus.
In the next phase of their research, the Stagljar lab plans to test the action of their inhibitors in an animal model of cystic fibrosis. If successful, the therapeutics may provide an avenue for the treatment of this debilitating disease.

Arnoldo A, Curak J, Kittanakom S, Chevelev I, Lee VT, Sahebol-Amri M, Koscik B, Ljuma L, Roy PJ, Bedalov A, Giaever G, Nislow C, Merrill RA, Lory S, Stagljar I. Identification of small molecule inhibitors of Pseudomonas aeruginosa exoenzyme S using a yeast phenotypic screen. PLoS Genet. (2008) 4(2):e1000005.

Igor Stagljar

30 April 2008

Lewis Kay wins $500,000 Premier's Discovery Award In Life Sciences and Medicine for his research on biomolecular NMR

The Premier’s Discovery Awards celebrate the research excellence of Ontario’s most accomplished researchers by highlighting their individual achievements and demonstrating Ontario’s attractiveness as a global research centre.
Nominees are evaluated on the impact of their work and its contributions to Ontario’s economy and society, and the extent of their international recognition.

The following is an excerpt from the announcement by the Ontario Ministry of Research and Innovation:

Dr. Lewis Kay is a brilliant scientist with an international reputation in the field of biomolecular nuclear magnetic resonance, a technology that uses magnetic fields to study the structures of medically important molecules by measuring how these structures change over time due to molecular interactions. Dr. Kay is an accomplished biochemist and has been instrumental in developing new three and four dimensional nuclear magnetic resonance (NMR) methods. Dr. Kay's work has revolutionized the field, making it possible for scientists to understand the components of individual molecules. His discoveries are providing new insights into how living systems grow and develop. They also improve techniques for protecting those systems, leading to knowledge about how to prevent illness. The methods developed by Dr. Kay are in use in biological NMR laboratories around the world, including labs researching illnesses such as cancer, diabetes and cardiovascular disease.

Lewis Kay