Seminars

Winter 2018

The seminars are held on Wednesdays at 12:30pm in the lecture room GB03 in wing B

(Click on the green bar to find out more about the speaker and the topic)

January 10, 2018 - Dr. John Aitchison, Inst. System Biology, Seattle

Dr. John Aitchison is President and Director at the Center for Infectious Disease Research.   He also holds an appointment as Professor at the Institute for Systems Biology. As a student, he studied biochemistry, specializing in biotechnology and genetic engineering at McMaster University in Ontario, Canada. There, in the laboratory of Dr. Richard Rachubinski, he investigated the molecular mechanisms responsible for sorting proteins into peroxisomes. After receiving his PhD, Dr. Aitchison performed his postdoctoral work in the laboratory of Nobel Laureate Dr. Günter Blobel at Rockefeller University. In Dr. Blobel’s lab, Dr. Aitchison applied classic cell biology techniques and yeast genetics to the study of protein import into the nucleus. During this time, he began to apply large-scale proteomics to the problem, which he continued as an Assistant Professor in the Faculty of Medicine and Dentistry at the University of Alberta until joining the ISB as a founding faculty member in 2000.

Dr. Aitchison’s laboratory exploits systems-based assays and analyses to reveal and understand complex biological phenomena. For much of his career, his lab has focused on yeast as a model for developing systems biology approaches. He joined the Center for Infectious Disease Research in 2011 with the goal of bringing systems biology to infectious disease research and using the challenges of infectious diseases to further develop systems biology.  Dr. Aitchison maintains a joint position at ISB and CID Research, building a partnership between the two organizations and remaining at the cutting-edge of systems biology while bringing new developments to infectious disease research.

Dr. Aitchison also holds affiliate appointments at the University of Washington, University of Alberta, and University of British Columbia and Rockefeller University. He is a member of the Molecular and Cellular Biology and BPSD at the University of Washington.

Title: Systems cell biology: From organelle biogenesis in yeast to global health
January 17, 2018 - Dr. Brenda Bass, University of Utah

ABSTRACT: Viruses produce double-stranded RNA (dsRNA) during infection, and long dsRNA is also encoded and expressed in animal cells. dsRNA-binding proteins (dsRBPs) are not sequence specific, and we are interested in how cells discriminate cellular from viral dsRNA.

Ongoing studies are focused on the mechanisms by which two dsRBPs, ADAR and Dicer, mediate "self" versus "non-self" discrimination. Our studies indicate that in C. elegans, the ADAR RNA editing enzyme marks cellular long dsRNA as “self”. Studies of D. melanogaster Dicer-2 indicate its helicase domain is specialized for cleavage of viral, or "non-self", dsRNA.

Title: Is that my double-stranded RNA or yours?
January 31, 2018 - Dr. Linda Chelico, University of Saskatchewan
The APOBEC family of enzymes are single-stranded polynucleotide cytidine deaminases. These enzymes catalyze the deamination of cytidine in RNA or single-stranded DNA, which forms uracil. From this eleven member enzyme family in humans, the deamination of single-stranded DNA by the Chelico lab focuses primarily on the seven APOBEC3 family members. The APOBEC3 family has many roles such as, restricting endogenous and exogenous retrovirus replication and retrotransposon insertion events and reducing DNA-induced inflammation. Similar to other APOBEC family members, the APOBEC3 enzymes are a double-edged sword that can catalyze deamination of cytosine in genomic DNA, which results in potential genomic instability due to the many mutagenic fates of uracil in DNA. Here we discuss how these enzymes find their single-stranded DNA substrate in different biological contexts such as during Human Immunodeficiency Virus (HIV) proviral DNA synthesis and the “off-target” genomic DNA substrate. The enzymes must be able to efficiently deaminate transiently available single-stranded DNA during reverse transcription, replication, or transcription. Specific biochemical characteristics promote deamination in each situation to increase enzyme efficiency through processivity, rapid enzyme cycling between substrates, or oligomerization state. The use of biochemical data to clarify biological functions and alignment with cellular data is discussed.
Title: For better or worse: Antiviral mechanisms of the APOBEC3 deoxycytidine deaminases
February 7, 2018 - Dr. Jessica Tyler, Weill Cornell Graduate School of Medical Sciences, NY
Our goal is to discover and understand the mechanistic basis of epigenetic regulation of aging, genomic integrity and gene expression. The most fundamental level of epigenetic regulation is provided by the packaging of our DNA together with histone proteins to make chromatin, and the opposite process of removal of histones from the DNA. These chromatin assembly and disassembly processes physically block or permit, respectively, access of the cellular machinery to the genetic information carried by our DNA, thereby playing a critical role in controlling all genomic processes. We focus on understanding how chromatin is disassembled and reassembled by histone chaperone proteins, ATP-dependent chromatin remodeling machines and post-translational modifications of the globular domains of the core histones, in order to discover new mechanisms whereby chromatin regulates aging, gene expression and genomic integrity. Our studies use a combination of molecular genetics in budding yeast, tissue culture studies, biochemistry and biophysical approaches. The proteins and processes that we study are so highly conserved through eukaryotic evolution, that what we learn in the highly genetically malleable yeast system is directly relevant to the situation in humans. In addition to learning how chromatin regulates fundamental processes in the cell, our studies are helping us to understand how defects in the chromatin structure lead to gene dysfunction and genomic instability, in turn causing human aging and disease states including cancer and leukemia.
Title: Regulation of genome stability and aging by chromatin assembly/disassembly
February 14, 2018 - Dr. Rosie Redfield, University of British Columbia

Do bacteria really have genetic exchange mechanisms, or do they just have processes that occasionally cause genetic exchange by accident?  We are using a variety of approaches to clarify the functions of bacterial conjugation, transduction and transformation systems, focusing especially on the natural transformation system of Haemophilus influenzae. Our latest work addresses how natural selection acts on the Gene Transfer Agent genes of Rhodobacter capsulatus, which encode a phage-like particle that transfers small fragments of chromosomal DNA.

Title:  Gene Transfer in Bacteria
February 28, 2018 - Dr. Stephen Withers, University of British Columbia
Carbohydrates play important roles in biological systems, not only in the form of energy storage materials such as starch, but also as “recognition elements” on cell surfaces. The degradation of such sugar structures is achieved using enzymes known as glycoside hydrolases (glycosidases). Specific enzyme inhibitors are not only useful tools for understanding enzyme mechanisms, but also can play important roles as therapeutics if inhibition suppresses unwanted reactions. In this talk I shall discuss our efforts to discover new inhibitors of human pancreatic alpha-amylase (HPA) that have potential in the control of blood sugar levels, thus in the treatment of diabetes and possibly obesity. High-throughput screening of natural product extract libraries from terrestrial and marine sources, in conjunction with my colleague Ray Andersen, has yielded two new classes of potent (Ki = 8 nM and 10 pM) inhibitors of human-amylase.  The first compound, Montbretin A, was isolated from the beautiful Crocosmia plant and its inhibition characterized through degradation studies and through X-ray crystallographic analysis of its complex with HPA in conjunction with Gary Brayer1. Subsequent animal studies revealed, good control of blood glucose levels in diabetic rats when administered orally2. The second screen revealed helianthamide as a highly potent peptidic inhibitor of HPA, derived from a sea anemone3. Structural studies with these inhibitors reveal a new paradigm for glycosidase inhibition in which pairs of aromatic moieties joined via a short linker provide the key inhibitory motif. Synthesis of simple mimics of this core structure has yielded inhibitors with Ki values ranging down to 50 nM to date, while screening of very large libraries of cyclic peptides through ribosome display methodologies in conjunction with the Suga group has produced two sets of inhibitors with Ki values between 1 and 10 nM, with similar modes of inhibition4.
Title: Discovery, design and development of human amylase inhibitors: from nM to pM
March 7, 2018 Dr. Joyce McBeth, University of Saskatchewan

Petroleum hydrocarbon (PHC) plumes are a common groundwater problem globally. Though environmental microbes effectively degrade PHCs in groundwater and generally limit the spatial extent of PHC plumes to a few hundred meters, it is often difficult to completely remediate PHC near the original source area, likely due to diffusion of PHCs sorbed to the aquifer sediments. In this study we examined a PHC-contaminated site in Saskatoon, SK. We have injected sources of phosphate, fixed nitrogen, and iron into the groundwater to stimulate growth of indigenous PHC-degrading microbes and biodegradation of the residual PHC. We used high-throughput amplicon sequencing (SSU rRNA gene) to track microbial community changes in the groundwater and metabolite analyses to track PHC degradation. Our results show that, in groundwater from the PHC-contaminated regions of the site, relatives of numerous genera of Fe(III)-reducing bacteria dominate the microbial communities and there are high concentrations of PHC metabolites in the groundwater. Many of the microbes we identified are closely related to bacteria that are known to couple PHC oxidation to Fe(III)-reduction. Managing environmental conditions to support the growth of these communities of iron-reducing microbes is a promising approach to remediate recalcitrant PHC contamination at this site.

Title: Bioremediation of a hydrocarbon plume through biostimulation of iron-reducing bacteria with a taste for gasoline
March 14, 2018 - Dr. Jae Jung, University of Southern California - CANCELLED
Title: CANCELLED
March 21, 2018 - Dr. Joelle Pelletier, University of Montreal

Trimethoprim is an antibiotic that clinically used worldwide. However, its utility is threatened by the emergence of Type II microbial dihydrofolate reductases (DfrB) that are natively trimethoprim-resistant. Upon whole-genome sequencing of trimethoprim-resistant E. coli from clinical isolates, we identified the dfrB4 gene flanked by multiple resistance genes, supporting its clinical emergence. To this effect, we initiated a drug discovery program for these new targets. Fragment-based inhibitor development has led to discovery of symmetrical bis-benzimidazoles that exhibit micromolar inhibition of DfrB1. We determined that all Type II DHFRs reveal similar inhibition patterns, broadening the utility of these inhibitors to the entire enzyme class.

We then apply molecular dynamics-based computational methods to predict the trajectory of ligand entry into the active-site cavity of a cytochrome P450. We successfully predict, in one single simulation, all residues known to be important for fatty acid substrate binding, thus confirming predictive accuracy. The simulations allow accurate docking of diverse substrates, as opposed to standardly used docking methods that are based on fixed crystal structure coordinates. These new computational biology approaches show promise to guide efforts to identify functional hotspots for mutation.

Title: An experimental and computational look at binding inhibitors and new substrates to enzymes
March 28, 2018 - Dr. Dennis Thiele, Duke University School of Medicine

Virtually all humans inhale the fungal pathogen Cryptococcus neoformans every day, as it resides in the soil, on trees and in bird guano, where it is aerosolized as desiccated yeast or spores.  Alveolar macrophages and other innate immune cells work to control C. neoformans proliferation in the lung, the primary site of infection,  but survival and colonization leads to pneumonia and dissemination to the brain, causing lethal meningitis. Our previous studies showed that for lung colonization C. neoformans must detoxify copper (Cu) via expression of the high capacity Cu-binding metallothionein (MT) proteins (1). In turn, in the brain C. neoformans must acquire Cu through the cell surface integral membrane high affinity Cu+ transporters, Ctr1 and Ctr4 (2,3). Curiously, a single Cu-sensing transcription factor, Cuf1, activates MT gene expression under high Cu conditions and Ctr1/Ctr4 expression during Cu limitation. This presentation will outline the rich new biology of Cu metabolism in C. neoformans that is driven by Cuf1 during Cu limitation, as elucidated by genome-wide studies. The orchestration of a novel Cu acquisition pathway, and a sophisticated cellular stress adaptation mechanism by Cuf1 is essential for virulence. Together, these studies highlight Cu metabolism as an area of potential therapeutic targets to address the dearth of efficacious antifungal agents (4).

References:

  1. Ding, C., Festa, R.A., Chen, Y.-L., Espart, A., Palacios, O., Espin, J., Capdevilla, M., Atrian, S. Heitman, J. and Thiele, D.J. (2013) Cryptococcus neoformans copper detoxification machinery is a critical fungal virulence factor. Cell Host & Microbe 13: 265-276.
  2. Tian-Shu Sun, T.-S., Ju, X., Gao,H.-L., Wang, T., Thiele, D.J., Li, J.Y., Wang, Z.-Y. and Ding, C. (2014) Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis. Nature Communications Nov 24; 5:5550. doi: 10.1038/ncomms6550.
  3. Smith, A.D., Logeman, B.L. and Thiele, D.J. (2017) Copper Acquisition and Utilization in Fungi. Annual Reviews of Microbiology 71: 597-623.
  4. García-Santamarina, S. and Thiele, D.J. (2015) Copper at the Fungal Pathogen-Host Axis.  J. Biol Chem. 290 (31):18945-18953.
Title: Mechanisms for coping with copper deficiency as targets for fungal pathogenesis
March 29, 2018 - Dr. Guido Silvestri, Emory University, Atlanta, Georgia - CANCELLED
Title: CANCELLED
April 4, 2018 - Dr. Kalle Gehring, McGill University
Protein phosphorylation and ubiquitination are widespread mechanisms for controlling protein activity. By influencing charge and conformation, they induce changes in protein biological activity and interactions with binding partners. The process of mitochondrial quality control is at the intersection of these pathways. PINK1, a protein kinase, and Parkin, an E3 ubiquitin ligase together regulate the disposal of damaged mitochondria by autophagy. When depolarized or damaged, mitochondria accumulate PINK1 which then phosphorylates ubiquitin to recruit cytosolic Parkin. In a second step, PINK1 phosphorylates Parkin leading to the recruitment of the downstream autophagic machinery.Normally quiescent due to autoinhibitory interactions, Parkin is activated by phosphorylation of its Ubl domain. The molecular mechanisms that activate its E2-binding and catalytic sites have been the focus of much speculation. Here, we report the crystal structure of the active conformation of Parkin. Phosphorylation of the Ubl domain by PINK1 leads to a major conformational change to unleash Parkin ligase activity. The work redefines the role of the Ubl domain and opens up new avenues for the identification of small molecules to activate the PINK1-Parkin pathway.
Title: Parkin and PINK1 at the crossroads of cell signalling by phosphorylation and ubiquitination
April 11, 2018 - Dr. Ravi Chibbar, University of Saskatchewan
Room change to E 1130, Health Sciences
Recently new food habits and sedentary lifestyles have led to an overconsumption of calories (>11.3 MJ/day) and an increase in diet-related diseases, such as type2 -diabetes, coronary heart disease and colorectal cancer. To overcome the rising cost of healthcare in developed countries reduction in the daily calorie intake is needed. Conversely, people in developing countries need food that is completely digested to provide the maximum calories to meet the energy requirements for normal body functions. Therefore, grain quality is dynamic and the improvement targets change with the consumer. More than 50 % of the calories in human diets are provided by the cereal grains wheat, maize, rice, barley, sorghum and millets. Carbohydrates are the predominant food component in these grains and the major source of energy (9.2 MJ/day). Most of the carbohydrates are found in the large endosperm tissue, where they occupy up to three-fourths of the space followed by proteins and lipids. The major carbohydrate starch is stored as an energy-dense and water-insoluble granule composed of onequarter amylose and three-quarters amylopectin along with traces of lipids and proteins. Like most carbohydrates, starches of various botanical sources show structural diversity and small changes in their makeup can alter functional properties. For example, amylose deficient (waxy) and increased amylose wheat and barley grain starches show differences in the timing of energy release in form of calories when passed through the human digestive tract. Thus, starch is an important target for cereal improvement to satisfy the demand for lower and higher energy foods for different market needs. Some of the targets for starch modification include alterations to starch granule size and amylopectin fine architecture which both influence starch digestibility. Other grain genetic improvement targets for human health include structural polysaccharides, such as dietary fibre and beta-glucan, which have an effect on lowering the calorie uptake. Gene-based markers associated with high beta-glucan concentration in barley are used to select suitable barley germplasm for breeding of barley with desirable beta-glucan content.
Title: Genomics strategies to improve grain carbohydrates for improved human health and diversification of cereal crops utilization
April 18, 2018 - Dr. Natalie Goto, University of Ottawa

Current research in the Goto lab focuses on the study of proteins that work at the cell membrane.  One of these targets is an intramembrane protease called the GlpG rhomboid that is able to catalyze the hydrolysis of peptide bonds in parts of proteins that are normally embedded in the membrane.  The Goto lab is working to understand how these substrates gain access to the catalytic site of the rhomboid, and how catalysis can be modulated through interactions with other domains that are distant from the active site, yet seem to influence its activity.  The lab also works on a fascinating group of bacterial cell division proteins that undergo dynamic pattern formation on lipid bilayers through a series of unusual conformational transformations.  For both research themes, unique insights into protein structure and dynamics at the atomic level are provided by solution NMR, a technique that can be applied to a wide range of conformationally exchanging systems.

Title: Deciphering the conformational choreography of Min proteins in bacterial cell division
April 26, 2018 - Dr. Nathan Peters, University of Calgary
Title: TBD