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Max Gruber - Past Lectures Archive

2018: Cisca Wijmenga
2018: Cisca Wijmenga

University Medical Center Groningen
Lodewijk Sandkuijl Professor of Human Genetics

Title: "We and our small friends: the ins and outs of our gut microbiome"

The human gut microbiome plays a major role in the production of vitamins, enzymes, and other compounds that regulate our metabolic and immune systems. To study the factors that affect the interaction between host and environmental and exogenous factors we have built LifeLines-DEEP, a multi-omics biobank that is part of LifeLines; Lifelines is a large population-based longitudinal cohort study in the northern part of Netherlands and includes 167,000 participants from which approximately 2000 phenotypes are collected per person. LifeLines-DEEP consists of 1,500 individuals (42% males, age range 18-81 years) for whom we have dietary, genetic, gut microbiome, immune and metabolic profiles. Our LifeLines-DEEP data show that the gut microbiome is a complex ecosystem influenced by many factors, including genetics, intrinsic factors, diet, medication and environmental factors; the non-genetic factors have a much stronger impact on the composition and diversity of gut microbes than host genetic factors.


2017: Jonathan Weissman
2017: Jonathan Weissman

University of California, San Francisco
Howard Hughes Medical Institute

Title: "Monitoring translation in time and space with ribosome profiling"

This talk will center around recent applications of ribosome profiling including the identification of novel protein coding regions, the demonstration of the principle of proportional synthesis of subunits in multiproteincomplexes, and monitoring localized protein translation.

In addition, recent findings will be shown related to the identification and characterisation of the ribosome quality control (RQC) complex, which is responsible for degrading nascent chains from failed translation reactions. This will include our discovery of a remarkable mechanism for tagging such nascent chains with carboxy-terminal alanine and threonine extensions (CAT tails) through a noncanonicaltranslation reaction that is independent of mRNA or 40S subunits.


2016: Judy Armitage
2016: Judy Armitage

Department of Biochemistry, University of Oxford

Title: "Choreography of bacterial proteins revealed by live cell imaging"

It is now clear that bacteria are not bags of diffusing chemicals, dividing in the middle to produce 2 daughter cells, but highlyorganisedorganisms. Many bacterial species swim by rotating helical flagella, biasing their swimming direction to an optimum environment for growth using a complex chemosensory system. Using live cell imaging, molecular genetics and biophysics we havecharacterisedtheremodellingof both the bacterial flagellar motor and relatedinjectisome, showing both undergo protein exchange while functioning, and this relates to their current environment. On division daughter cells need to have the correct complement of chemosensory proteins to control flagellarbehaviourand compete in changing environment. We havecharacterisedthe relationship between the segregation of the 2 Rhodobactersphaeroides chromosomes, the chemosensorysignallingcomplexes and septum formation and revealed a complex interrelationship. Together these projects illustrate the complexity of bacterial growth andbehaviour, and perhaps novel targets for controlling bacterialcolonisation.


2015: Piet Gros
2015: Piet Gros
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research Dept. Chemistry, Utrecht University

Title: "In the right place at the right time: Molecular regulation by the complement system in immune defense"

The complement system is an important arm of the mammalian immune defense in blood and interstitial fluids. Complement is formed by ~30 large multi-domain plasma proteins and cell-surface receptors. Together these proteins enable the host to recognize, lyse and clear invading microbes and altered host cells, while protecting healthy host cells and tissue.

We have studied the molecular mechanisms of recognition and regulation of the multi-component protein regulatory pathways formed by the complement system. Through several crystallographic studies we revealed the mechanisms at work in the amplification loop of complement. Recent data provide insights into the host protection mechanisms that protect healthy host cells from complement attack. Using EM tomography we demonstrated the formation of immune complexes that initiate complement. Overall, our data highlight principle mechanisms that are employed by regulatory pathways to ensure localization, initiation, amplification and inhibition, i.e. to ensure activity at the right place and time.

Key references:
M.A. Hadders, D. Bubeck et al. Cell Reports 1, 200-207 (2012)
C. Diebolder, F. Beurskens et al., Science 343, 1261-1263 (2014)


2014: Petra Schwille
2014: Petra Schwille

2014: Petra Schwille

Cellular and Molecular Biophysics, Max Planck Institute of Biochemistry, Martinsried, Germany
Title: "Bottom-Up Synthetic Biology of Cell Division"

Biological cells, the minimal units of life, are highly complex entities. Yet life must have started much simpler, at some unknown time long ago, and with unknown components. Based on today's knowledge of physics, chemistry and biology, our goal is to reconstitute conditions that   allow biological molecules to settle into self-organized and self-reproducing systems, thus establishing preconditions for life in a bottom-up synthetic biology approach. In this context  we explored the reconstitution of the essential first steps of -bacterial- cell division in a cell-free system, consisting of only a few protein species, an energy source and a membrane compartment. We were able to establish and quantitatively elucidate the self-organization of the (contractile) Z ring positioning machinery, MinCDE, into waves and oscillations, the formation of FtsZ protorings at the membrane and their positioning to the geometric center of the compartment. Furthermore, we systematically studied the influence of various physical and   chemical cues on pattern and gradient formation to establish a better understanding of the fundamental requirements for correct orchestration of the bacterial cell division machinery in space and time.


2013: Bernd Bukau
2013: Bernd Bukau
2013: Bernd Bukau

Zentrum fur Molekulare Biologie der Universität Heidelberg (ZMBH)

Title: "Cellular strategies for coping with protein aggregation"

Protein aggregation is an organized process in all cells from bacteria to human, leading to the deposition of aggregates at specific sites. Such sequestration of misfolded proteins can be protective for cell function, presumably by facilitating activities of the protein quality control network and by sequestering harmful protein species. Cells can remove aggregates by either degradation or disaggregation and refolding of aggregated polypeptides to the native state. Disaggregation in bacteria, yeast and plant cells requires the joint action of a disaggregase of the Hsp100 family (ClpB in bacteria or Hsp104 in yeast) and Hsp70 with its co-chaperones. This bichaperone system extracts individual polypeptides from the aggregate which are then threaded through the central pore of the disaggregase and refolded to the native state. Hsp70 acts by targeting Hsp100 to aggregates and activating the threading activity, involving the middle domain of Hsp100 as a toggle. However, Hsp100 disaggregases are lacking in animal cells and thus it has been a mystery whether and how aggregates can be resolubilized. A potent disaggregating activity in metazoa is provided the cooperating action of Hsp70 and Hsp110. This seminar will descibe principles of aggregate formation in yeast cells as well as mechanisms of protein disaggregation in bacteria, yeast and human cells.


2012: William T. Wickner
2012: William T. Wickner
2012: William T. Wickner

Dartmouth Medical School, Hanover, NH, USA

Title: "Studying membrane fusion with yeast vacuoles: 5 lipids, 4 SNAREs, 3 chaperones, 2 nucleotides and a RabGTPase, all dancing in a ring"

Wickner has developed yeast vacuoles as a paradigm of membrane fusion in endocytic and exocytic traffic. Each stage of this traffic, from yeast to humans, uses similar Rabs, effector complexes, SNAREs, and SNARE chaperones. In addition to studying vacuole fusion in vivo and in vitro, Wickner reconstituted proteoliposome fusion with all-purified components. This system has revealed detailed basic features of the underlying fusion mechanism, which will be discussed. In addition, several fusion catalysts have been identified that undergo regulated cycles,including. HOPS and Sec17/18p, which synergistically support fusion as SNAREs cycle between cis-complexes, the uncomplexed state, and trans-complexes, and the vacuolar kinase Yck3p and unknown phosphatase(s) that regulate HOPS phosphorylation. Understanding the vacuolar HOPS complex, discovered and studied in this work, underlies studies of human arthrogryposis, renal dysfunction, and cholestasis syndromes, caused by mutations in the human VPS33 gene. Human HOPS has recently been shown to have a unique and central role in Marburg and Ebola virus invasion of human cells.


2011: Sandra L. Schmid
2011: Sandra L. Schmid
2011: Sandra L. Schmid


Scrips, La Jolla, CA, USA

Title: "Dynamin, the brains and brawn of clathrin-mediated endocytosis"

Clathrin mediated endocytosis (CME) is initiated by the assembly of coat proteins, clathrin and adaptors to form nascent clathrin coated pits (CCPs). As they grow, CCPs gain curvature and invaginate until connected by narrow necks, which undergo fission to release clathrin coated vesicles (CCVs). Live cell imaging of GFP-clathrin using total internal reflection fluorescence microscopy (TIR-FM) has shown that a large subpopulation of nascent CCPs are aborted, leading to the suggestion that an endocytosis ‘check-point’ monitors the fidelity of CCP maturation and regulates entry into the cell. The large GTPase, dynamin is essential for CME.  As the ‘brains’ it functions to monitor the fidelity of early stages in CCV formation and to control the endocytosis checkpoint.  As the ‘brawn’ dynamin uses its mechanochemical activity to catalyze membrane fission. Interestingly, differential in vivo and in vitro properties of two closely related dynamin isoforms, the neuron-specific dynamin1 and the ubiquitously expressed dynamin2, suggest that they are ideally suited to differentially regulate CME in neurons and nonneuronal cells.


2010: Wolfgang Baumeister
2010: Wolfgang Baumeister
2010: Wolfgang Baumeister


Max Planck Institut, Martinsried, Germany

Title: "Electron Cryomicroscopy: From Molecules to Systems"

Single particle electron microscopy has become a powerful method for studying large protein complexes and, in conjunction with other biochemical and biophysical methods, can provide structural models at (pseudo) atomic resolution. This will be exemplified with two proteolytic complexes of extraordinary size, tripeptidyl peptidase II (6 MDa) and the 26S proteasome (2.5 MDa). Electron cryotomography enables the structural analysis of non-repetitive supramolecular structures, such as organelles or even whole cells providing unprecedented insights into their supramolecular organization. In conjunction with subtomogram classification and averaging molecular structures can be studied in situ, i.e. in their functional environment. Studies with polyribosomes or quiescent ribosomes will illustrate the potential of this new approach to structural cell biology.


2009: John E. Walker - Nobel Prize Winner Chemistry

Medical Research Council Mitochondrial Biology Unit, Cambridge, UK

The mosaic structure of ATP synthase

Structural  biology techniques are being used to analyze highly complex protein structures built up from multiple polypeptide chains. One approach is to combine different structural methods to obtain an overall structure. An example of the application of this approach is provided by the ATP synthase complex from mitochondria, a membrane bound structure assembled from thirty polypeptide chains of seventeen different kinds. The enzyme has been purified and resolved biochemically into smaller domains, and these component structures have been determined by X-ray crystallography. Other domains and subunits have been produced by recombinant expression in bacteria, and their structures have been solved by either X-ray crystallography or solution nuclear magnetic resonance methods. These component structures have been assembled within the framework of a low resolution overall structure determined by electron cryo-microscopy of single enzyme complexes, thereby providing an overall mosaic structure. This overall structure has provided the basis for showing that the enzyme is a molecular engine in which the proton motive force across the inner membrane of the mitochondrion is coupled to the chemical synthesis of ATP from ADP and phosphate by a mechanical rotary mechanism, akin to the action of the Wankel motor car engine. It is becoming increasingly apparent that the ATP synthase complexes themselves are organised in arrays, possibly with other enzyme complexes, in the inner membranes of mitochondria, and that these higher order arrangements influence the overall structure and functions of the mitochondrion itself.


2008: Jan H.J. Hoeijmakers
Department of Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
DNA damage and its impact on cancer and aging

The instructions for life are laid down in the genetic information contained within the DNA molecule that harbors all our genes and is located in the nucleus of every cell of our body.  Importantly, these instructions should function properly during the entire life span of an organism and should be transmitted faithfully over subsequent generations. However, ubiquitous DNA-damaging agents such as UV light and X-rays and numerous natural and man-made chemicals continuously threaten DNA integrity. In addition, DNA suffers constantly from the damaging effects of reactive oxygen species generated by our own respiration. Moreover, DNA has an intrinsic chemical instability, leading to spontaneous loss of coding information. Spectacular progress in recent years has revealed the dramatic impact of DNA damage on human health and identified damage to DNA as a major cause of onset of cancer, ageing and inherited defects. Ingeniously, to prevent the deleterious consequences of DNA injury the DNA carries also instructions for its own care-taking apparatus. An important component of this self-protecting mechanism is comprised of an intricate network of DNA damage repair systems. These systems attempt to repair the DNA lesions before they give rise to permanent changes in the genetic code leading to cancer and inborn defects or cause cell death or permanent growth arrest contributing to ageing. One of the most versatile repair pathways is called nucleotide excision repair. Patients carrying inborn defects in this repair process suffer from extreme sensitivity to UV radiation in sunlight and to many chemical agents, frequently develop cancer and some patients exhibit dramatic signs of premature aging. The lecture will highlight our current understanding of DNA damage, repair and the overall condition of our genes from studies involving transgenic mice and the impact of DNA damage and repair on health, cancer, aging-related diseases and longevity.


2007: Douglas Rees
Division of Chemistry and Chemical Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, USA
The Structural Basis of Biological Nitrogen Fixation

Nitrogenase catalyzes the enzymatic reduction of atmospheric dinitrogen to ammonia during the process of biological nitrogen fixation.  Nitrogenase consists of two component metalloproteins, the iron (Fe-) protein and the molybdenum-iron (MoFe-) protein, that together mediate the ATP-hydrolysis dependent reduction of substrates to products. Striking parallels are evident in the interaction of nucleotides with the Fe-protein and a broad class of nucleotide binding proteins involved in transport, signal and energy transduction processes. Recent developments in the structural characterization of the nitrogenase system will be presented, emphasizing the structures of complexes between the component proteins  that are relevant to the coupling of ATP hydrolysis to interprotein electron transfer, and a very high resolution crystallographic analysis of the MoFe-protein establishing a previously unrecognized light atom ligand in the center of the active site FeMo-cofactor. Together with kinetic, spectroscopic and synthetic model compound studies, these structures provide a framework for addressing the mechanism of substrate reduction by nitrogenase.


2006: Wilfred F. van Gunsteren
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zürich, ETH Zürich, Switzerland

Computer simulation of the dynamics of biomolecular systems by the molecular dynamics (MD) technique yields the possibility of describing the structure-energy-function relationships of molecular processes in terms of interactions at the atomic level. Important processes or thermodynamic equilibria are governed by weak (non-bonded) forces: polypeptide folding, biomolecular association, partitioning between solvents and membrane or micelle formation. When modeling these processes four problems must be addressed: the force field problem, the search problem, the ensemble problem and the experimental problem. These will be discussed and illustrated with examples. Developments to enhance the accuracy and time scale of biomolecular simulations will be addressed.


2005: Bernard Witholt
Institute of Biotechnology, ETH Zürich, Switzerland
White Biotechnology, Biomass and the Future

The use of bioprocesses in the chemical industry has developed gradually in the past few decades. Such processes have been around since the first half of the 20th Century, starting with European fermentation processes for the production of ethanol, butanol, acetic acid, and citric acid. Japan built up a vigorous fermentation industry in the 50’s and 60’s that produced amino acids, vitamins and nucleotides. Today, a bioprocess sector is developing in Europe, the US, Japan and China, which aims at the synthesis of fine chemicals, chiral drug intermediates and is also moving towards bulk chemicals such as acrylamide (Japan), lactic acid (Cargill, US) and propanediol (Dupont, US). This sector has recently been baptized “White Biotech”, and is seen by some as the next major biotechnology wave. Since White Biotech for bulk chemicals will be dependent on agro resources, its development will affect not only the chemical industry, but will also lead to the emergence of a significant agro-chemical sector.

Another sector that has received considerable attention lately is Biomass, which is seen as a major contributor to the alternative energy package of geothermal, wave, wind, solar and biobased energy generation technologies. Biomass options include the use of waste biomass, controlled reforestation and energy rich crops as energy sources. Major programs have developed around biodiesel and bioethanol, the latter especially powerful in Brazil and Australia, based on sugar cane, and lately also in the US, based on corn starch.

The recognition of Biomass based Energy and the more recent emergence of White Biotech as important future technological resources will move these two areas towards the center of debates about agricultural priorities and future land use, water resources, and the long term sustainability of our Ecosystem. These debates will influence future government policies, industrial approaches and societal responses relating to Energy, Environment, Agrochemistry and Industrial Chemistry. Thus, it might be useful to examine a few alternative development scenarios to see which will best serve our future societal needs. The use of bioprocesses in the chemical industry has developed gradually in the past few decades. Such processes have been around since the first half of the 20th Century, starting with European fermentation processes for the production of ethanol, butanol, acetic acid, and citric acid. Japan built up a vigorous fermentation industry in the 50’s and 60’s that produced amino acids, vitamins and nucleotides. Today, a bioprocess sector is developing in Europe, the US, Japan and China, which aims at the synthesis of fine chemicals, chiral drug intermediates and is also moving towards bulk chemicals such as acrylamide (Japan), lactic acid (Cargill, US) and propanediol (Dupont, US). This sector has recently been baptized “White Biotech”, and is seen by some as the next major biotechnology wave. Since White Biotech for bulk chemicals will be dependent on agro resources, its development will affect not only the chemical industry, but will also lead to the emergence of a significant agro-chemical sector.

Another sector that has received considerable attention lately is Biomass, which is seen as a major contributor to the alternative energy package of geothermal, wave, wind, solar and biobased energy generation technologies. Biomass options include the use of waste biomass, controlled reforestation and energy rich crops as energy sources. Major programs have developed around biodiesel and bioethanol, the latter especially powerful in Brazil and Australia, based on sugar cane, and lately also in the US, based on corn starch.

The recognition of Biomass based Energy and the more recent emergence of White Biotech as important future technological resources will move these two areas towards the center of debates about agricultural priorities and future land use, water resources, and the long term sustainability of our Ecosystem. These debates will influence future government policies, industrial approaches and societal responses relating to Energy, Environment, Agrochemistry and Industrial Chemistry. Thus, it might be useful to examine a few alternative development scenarios to see which will best serve our future societal needs.


2004: Hidde L. Ploeg
Dept. of Pathology, Harvard Medical School, Boston, USA
Large viruses, small molecules and the biochemistry of protein quality control

Many pathogens owe their success to circumventing or compromising the host’s immune response. Large DNA viruses such as Pox- and Herpesviruses are true masters of deception and evasion. The Human Cytomegalovirus (HCMV) encodes a series of small glycoproteins that selectively target and destroy Major Histocompatibility (MHC)  proteins,  key glycoproteins essential for host defense.  The study of how these viral proteins handle the Class I MHC substrates has provided a detailed picture of a protein degradation pathway that is likely to be a more general route for disposal of unwanted proteins. In the course of these studies, the laboratory has made investments in the development of chemistry-based approaches to provide new analytical tools. We have further conducted high-throughput screens in the search of small molecules that might selectively interfere with protein quality control and degradation.  What has emerged is a tractable biological model for the study of glycoprotein synthesis, stability and metabolism, with an important role for synthetic chemistry. Some of the newly developed tools are readily applicable  to other biological questions.


2003: Ronald Plasterk
Hubrecht Laboratory, Utrecht, The Netherlands
RNAi and transposon silencing in C. elegans

C. elegans protects progeny against undesired DNA rearrangements by silencing transposition in the germline. We have found mutations in which this silencing is lost. Many of these are also defective in a phenomenon that is called RNA interference or RNAi: the silencing of gene expression after experimental application of double-stranded RNA. This field of research has recently exploded, when it turned out that the underlaying mechanism is almost universal, and found in fungi, plants and animals. Our current picture of the mechanism will be presented.


2002: Wim Hol
University of Washington, Seattle, USA
Medicinal Protein Crystallography and Structural Genomics for Tropical Diseases

2001: Piet Borst
Nederlands Kanker Instituut, Amsterdam, The Netherlands
Drug and Lipid Transporters: Biochemistry and Genetics

2000: Karl Stetter
University of Regensburg, Germany
Hyperthermophilic microorganisms

1999: Andreas Engel
Biozentrum Basel, Switzerland
Membrane Channels

1998: Alan Fersht
Cambridge University, UK
Chaperones and Minichaperones

1997: Ronald Kaback
Howard Hughes Medical Institute, LA, USA
The Lactose Permease of E.coli

1996: Joachim Frank
Wadworth Center New York, USA
Protein Synthesis in Three Dimensions

1995: Walter Wahli
University of Lausanne, Switzerland
Nuclear Hormone Receptors

1994: Hans Jansonius
University of Basel, Switzerland

Vitamin B6


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contact: maxgruber@rug.nl

Last modified:16 September 2019 4.48 p.m.