Project acronym ACCOMPLI
Project Assembly and maintenance of a co-regulated chromosomal compartment
Researcher (PI) Peter Burkhard Becker
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Advanced Grant (AdG), LS2, ERC-2011-ADG_20110310
Summary "Eukaryotic nuclei are organised into functional compartments, – local microenvironments that are enriched in certain molecules or biochemical activities and therefore specify localised functional outputs. Our study seeks to unveil fundamental principles of co-regulation of genes in a chromo¬somal compartment and the preconditions for homeostasis of such a compartment in the dynamic nuclear environment.
The dosage-compensated X chromosome of male Drosophila flies satisfies the criteria for a functional com¬partment. It is rendered structurally distinct from all other chromosomes by association of a regulatory ribonucleoprotein ‘Dosage Compensation Complex’ (DCC), enrichment of histone modifications and global decondensation. As a result, most genes on the X chromosome are co-ordinately activated. Autosomal genes inserted into the X acquire X-chromosomal features and are subject to the X-specific regulation.
We seek to uncover the molecular principles that initiate, establish and maintain the dosage-compensated chromosome. We will follow the kinetics of DCC assembly and the timing of association with different types of chromosomal targets in nuclei with high spatial resolution afforded by sub-wavelength microscopy and deep sequencing of DNA binding sites. We will characterise DCC sub-complexes with respect to their roles as kinetic assembly intermediates or as representations of local, functional heterogeneity. We will evaluate the roles of a DCC- novel ubiquitin ligase activity for homeostasis.
Crucial to the recruitment of the DCC and its distribution to target genes are non-coding roX RNAs that are transcribed from the X. We will determine the secondary structure ‘signatures’ of roX RNAs in vitro and determine the binding sites of the protein subunits in vivo. By biochemical and cellular reconstitution will test the hypothesis that roX-encoded RNA aptamers orchestrate the assembly of the DCC and contribute to the exquisite targeting of the complex."
Summary
"Eukaryotic nuclei are organised into functional compartments, – local microenvironments that are enriched in certain molecules or biochemical activities and therefore specify localised functional outputs. Our study seeks to unveil fundamental principles of co-regulation of genes in a chromo¬somal compartment and the preconditions for homeostasis of such a compartment in the dynamic nuclear environment.
The dosage-compensated X chromosome of male Drosophila flies satisfies the criteria for a functional com¬partment. It is rendered structurally distinct from all other chromosomes by association of a regulatory ribonucleoprotein ‘Dosage Compensation Complex’ (DCC), enrichment of histone modifications and global decondensation. As a result, most genes on the X chromosome are co-ordinately activated. Autosomal genes inserted into the X acquire X-chromosomal features and are subject to the X-specific regulation.
We seek to uncover the molecular principles that initiate, establish and maintain the dosage-compensated chromosome. We will follow the kinetics of DCC assembly and the timing of association with different types of chromosomal targets in nuclei with high spatial resolution afforded by sub-wavelength microscopy and deep sequencing of DNA binding sites. We will characterise DCC sub-complexes with respect to their roles as kinetic assembly intermediates or as representations of local, functional heterogeneity. We will evaluate the roles of a DCC- novel ubiquitin ligase activity for homeostasis.
Crucial to the recruitment of the DCC and its distribution to target genes are non-coding roX RNAs that are transcribed from the X. We will determine the secondary structure ‘signatures’ of roX RNAs in vitro and determine the binding sites of the protein subunits in vivo. By biochemical and cellular reconstitution will test the hypothesis that roX-encoded RNA aptamers orchestrate the assembly of the DCC and contribute to the exquisite targeting of the complex."
Max ERC Funding
2 482 770 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym ACTMECH
Project Emergent Active Mechanical Behaviour of the Actomyosin Cell Cortex
Researcher (PI) Stephan Wolfgang Grill
Host Institution (HI) TECHNISCHE UNIVERSITAET DRESDEN
Country Germany
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.
Summary
The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-12-01, End date: 2017-08-31
Project acronym BRAINEVODEVO
Project A Neuron Type Atlas of the Annelid Brain: Development and Evolution of Chemosensory-Motor Circuits
Researcher (PI) Detlev Arendt
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Country Germany
Call Details Advanced Grant (AdG), LS3, ERC-2011-ADG_20110310
Summary Neural circuits, composed of interconnected neurons, represent the basic unit of the nervous system. One way to understand the highly complex arrangement of cross-talking, serial and parallel circuits is to resolve its developmental and evolutionary emergence. The rationale of the research proposal presented here is to elucidate the complex circuitry of the vertebrate and insect forebrain by comparison to the much simpler and evolutionary ancient “connectome” of the marine annelid Platynereis dumerilii. We will build a unique resource, the Platynereis Neuron Type Atlas, combining, for the first time, neuronal morphologies, axonal projections, cellular expression profiling and developmental lineage for an entire bilaterian brain. We will focus on five days old larvae when most adult neuron types are already present in small number and large part of the axonal scaffold in place.
Building on the Neuron Type Atlas, the second part of the proposal envisages the functional dissection of the Platynereis chemosensory-motor forebrain circuits. A newly developed microfluidics behavioural assay system, together with a cell-based GPCR screening will identify partaking neurons. Zinc finger nuclease-mediated knockout of circuit-specific transcription factors as identified from the Atlas will reveal circuit-specific gene regulatory networks, downstream effector genes and functional characteristics. Laser ablation of GFP-labeled single neurons and axonal connections will yield further insight into the function of circuit components and subcircuits. Given the ancient nature of the Platynereis brain, this research is expected to reveal a simple, developmental and evolutionary “blueprint” for the olfactory circuits in mice and flies and to shed new light on the evolution of information processing in glomeruli and higher-level integration in sensory-associative brain centres.
Summary
Neural circuits, composed of interconnected neurons, represent the basic unit of the nervous system. One way to understand the highly complex arrangement of cross-talking, serial and parallel circuits is to resolve its developmental and evolutionary emergence. The rationale of the research proposal presented here is to elucidate the complex circuitry of the vertebrate and insect forebrain by comparison to the much simpler and evolutionary ancient “connectome” of the marine annelid Platynereis dumerilii. We will build a unique resource, the Platynereis Neuron Type Atlas, combining, for the first time, neuronal morphologies, axonal projections, cellular expression profiling and developmental lineage for an entire bilaterian brain. We will focus on five days old larvae when most adult neuron types are already present in small number and large part of the axonal scaffold in place.
Building on the Neuron Type Atlas, the second part of the proposal envisages the functional dissection of the Platynereis chemosensory-motor forebrain circuits. A newly developed microfluidics behavioural assay system, together with a cell-based GPCR screening will identify partaking neurons. Zinc finger nuclease-mediated knockout of circuit-specific transcription factors as identified from the Atlas will reveal circuit-specific gene regulatory networks, downstream effector genes and functional characteristics. Laser ablation of GFP-labeled single neurons and axonal connections will yield further insight into the function of circuit components and subcircuits. Given the ancient nature of the Platynereis brain, this research is expected to reveal a simple, developmental and evolutionary “blueprint” for the olfactory circuits in mice and flies and to shed new light on the evolution of information processing in glomeruli and higher-level integration in sensory-associative brain centres.
Max ERC Funding
2 489 048 €
Duration
Start date: 2012-03-01, End date: 2017-02-28
Project acronym CARDIOSPLICE
Project A systems and targeted approach to alternative splicing in the developing and diseased heart: Translating basic cell biology to improved cardiac function
Researcher (PI) Michael Gotthardt
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Country Germany
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary Cardiovascular disease keeps the top spot in mortality statistics in Europe with 2 million deaths annually and although prevention and therapy have continuously been improved, the prevalence of heart failure continues to rise. While contractile (systolic) dysfunction is readily accessible to pharmacological treatment, there is a lack of therapeutic options for reduced ventricular filling (diastolic dysfunction). The diastolic properties of the heart are largely determined by the giant sarcomeric protein titin, which is alternatively spliced to adjust the elastic properties of the cardiomyocyte. We have recently identified a titin splice factor that plays a parallel role in cardiac disease and postnatal development. It targets a subset of genes that concertedly affect biomechanics, electrical activity, and signal transduction and suggests alternative splicing as a novel therapeutic target in heart disease. Here we will build on the titin splice factor to identify regulatory principles and cofactors that adjust cardiac isoform expression. In a complementary approach we will investigate titin mRNA binding proteins to provide a comprehensive analysis of factors governing titin’s differential splicing in cardiac development, health, and disease. Based on its distinctive role in ventricular filling we will evaluate titin splicing as a therapeutic target in diastolic heart failure and use a titin based reporter assay to identify small molecules to interfere with titin isoform expression. Finally, we will evaluate the effects of altered alternative splicing on diastolic dysfunction in vivo utilizing the splice deficient mutant and our available animal models for diastolic dysfunction.
The overall scientific goal of the proposed work is to investigate the regulation of cardiac alternative splicing in development and disease and to evaluate if splice directed therapy can be used to improve diastolic function and specifically the elastic properties of the heart.
Summary
Cardiovascular disease keeps the top spot in mortality statistics in Europe with 2 million deaths annually and although prevention and therapy have continuously been improved, the prevalence of heart failure continues to rise. While contractile (systolic) dysfunction is readily accessible to pharmacological treatment, there is a lack of therapeutic options for reduced ventricular filling (diastolic dysfunction). The diastolic properties of the heart are largely determined by the giant sarcomeric protein titin, which is alternatively spliced to adjust the elastic properties of the cardiomyocyte. We have recently identified a titin splice factor that plays a parallel role in cardiac disease and postnatal development. It targets a subset of genes that concertedly affect biomechanics, electrical activity, and signal transduction and suggests alternative splicing as a novel therapeutic target in heart disease. Here we will build on the titin splice factor to identify regulatory principles and cofactors that adjust cardiac isoform expression. In a complementary approach we will investigate titin mRNA binding proteins to provide a comprehensive analysis of factors governing titin’s differential splicing in cardiac development, health, and disease. Based on its distinctive role in ventricular filling we will evaluate titin splicing as a therapeutic target in diastolic heart failure and use a titin based reporter assay to identify small molecules to interfere with titin isoform expression. Finally, we will evaluate the effects of altered alternative splicing on diastolic dysfunction in vivo utilizing the splice deficient mutant and our available animal models for diastolic dysfunction.
The overall scientific goal of the proposed work is to investigate the regulation of cardiac alternative splicing in development and disease and to evaluate if splice directed therapy can be used to improve diastolic function and specifically the elastic properties of the heart.
Max ERC Funding
1 499 191 €
Duration
Start date: 2012-01-01, End date: 2017-06-30
Project acronym CelluFuel
Project Designer Cellulosomes by Single Molecule Cut & Paste
Researcher (PI) Hermann Eduard Gaub
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Advanced Grant (AdG), LS1, ERC-2011-ADG_20110310
Summary Biofuel from wood and waste will be a substantial share of our future energy mix. The conversion of lignocellulose to fermentable polysaccharides is the current bottleneck. We propose to use single molecule cut and paste technology to assemble designer cellulosoms and combine enzymes from different species with nanocatalysts.
Summary
Biofuel from wood and waste will be a substantial share of our future energy mix. The conversion of lignocellulose to fermentable polysaccharides is the current bottleneck. We propose to use single molecule cut and paste technology to assemble designer cellulosoms and combine enzymes from different species with nanocatalysts.
Max ERC Funding
2 351 450 €
Duration
Start date: 2012-03-01, End date: 2018-02-28
Project acronym COMPLEX_TRAITS
Project High-throughput dissection of the genetics underlying complex traits
Researcher (PI) Lars Steinmetz
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Country Germany
Call Details Advanced Grant (AdG), LS2, ERC-2011-ADG_20110310
Summary The vast majority of genetic diseases are complex traits, conditioned by multiple genetic and environmental factors. Yet our understanding of the genetics underlying such traits in humans remains extremely limited, due largely to the statistical complexity of inferring the effects of allelic variants in a genetically diverse population. Novel tools for the dissection of the genetic architecture of complex traits, therefore, can be most effectively developed in model organisms, where the contribution of individual alleles can be quantitatively determined in controlled genetic backgrounds. We have previously established the yeast Saccharomyces cerevisiae as a model for complex traits by unravelling complex genetic architectures that govern quantitative phenotypes in this organism. We achieved this by pioneering approaches that have revealed crucial information about the complexity of the underlying genetics. Here we propose to advance to the next level of complex trait dissection by developing systematic, genome-wide technologies that aim to identify all of the variants underlying a complex trait in a single step. In particular, we will investigate traits involved in mitochondrial function, which are both clinically relevant and highly conserved in yeast. Our combination of genomic technologies will allow us to: 1) systematically detect, with maximal sensitivity, the majority of genetic variants (coding and non-coding) that condition these traits; 2) quantify the contributions of these variants and their interactions; and 3) evaluate the strengths and limitations of current methods for dissecting complex traits. Taken together, our research will yield fundamental insights into the genetic complexity of multifactorial traits, providing valuable lessons and establishing novel genomic tools that will facilitate the investigation of complex diseases.
Summary
The vast majority of genetic diseases are complex traits, conditioned by multiple genetic and environmental factors. Yet our understanding of the genetics underlying such traits in humans remains extremely limited, due largely to the statistical complexity of inferring the effects of allelic variants in a genetically diverse population. Novel tools for the dissection of the genetic architecture of complex traits, therefore, can be most effectively developed in model organisms, where the contribution of individual alleles can be quantitatively determined in controlled genetic backgrounds. We have previously established the yeast Saccharomyces cerevisiae as a model for complex traits by unravelling complex genetic architectures that govern quantitative phenotypes in this organism. We achieved this by pioneering approaches that have revealed crucial information about the complexity of the underlying genetics. Here we propose to advance to the next level of complex trait dissection by developing systematic, genome-wide technologies that aim to identify all of the variants underlying a complex trait in a single step. In particular, we will investigate traits involved in mitochondrial function, which are both clinically relevant and highly conserved in yeast. Our combination of genomic technologies will allow us to: 1) systematically detect, with maximal sensitivity, the majority of genetic variants (coding and non-coding) that condition these traits; 2) quantify the contributions of these variants and their interactions; and 3) evaluate the strengths and limitations of current methods for dissecting complex traits. Taken together, our research will yield fundamental insights into the genetic complexity of multifactorial traits, providing valuable lessons and establishing novel genomic tools that will facilitate the investigation of complex diseases.
Max ERC Funding
2 499 821 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym COMPLEXNMD
Project NMD Complexes: Eukaryotic mRNA Quality Control
Researcher (PI) Christiane Helene Berger-Schaffitzel
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Country Germany
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary Nonsense-mediated mRNA decay (NMD) is an essential mechanism controlling translation in the eukaryotic cell. NMD ascertains accurate expression of the genetic information by quality controlling messenger RNA (mRNA). During translation, NMD factors recognize and target to degradation aberrant mRNAs that have a premature stop codon (PTC) and that would otherwise lead to the production of truncated proteins which could be harmful for the cell. A wide range of genetic diseases have their origin in the mechanisms of NMD. Discrimination of a PTC from a correct termination codon depends on splicing and translation, and it is the first and foremost step in human NMD. The molecular mechanism of this process remains elusive to date.
In the research proposed, I will undertake to elucidate the molecular basis of translation termination and induction of NMD. I will study complexes involved in human translation termination at a normal stop codon and involved in NMD. I will employ an array of innovative techniques including recombinant production of human protein complexes by the MultiBac system, mammalian in vitro translation, mass spectrometry for detecting relevant protein modifications, biophysical techniques, mutational analyses and RNA-interference experiments. Stable ribosomal complexes with termination factors and complexes of NMD factors will be used for structure determination by cryo-electron microscopy. State-of-the-art image processing will be applied to address the inherent heterogeneity of the complexes. Hybrid approaches will allow the combination of cryo-EM structures with existing high-resolution structures of factors involved for generation of quasi-atomic models thereby visualizing molecular mechanisms of NMD action. This interdisciplinary work will foster our understanding at a molecular level of a paramount step in mRNA quality control, which is a vital prerequisite for the development of new treatment strategies in NMD-related diseases.
Summary
Nonsense-mediated mRNA decay (NMD) is an essential mechanism controlling translation in the eukaryotic cell. NMD ascertains accurate expression of the genetic information by quality controlling messenger RNA (mRNA). During translation, NMD factors recognize and target to degradation aberrant mRNAs that have a premature stop codon (PTC) and that would otherwise lead to the production of truncated proteins which could be harmful for the cell. A wide range of genetic diseases have their origin in the mechanisms of NMD. Discrimination of a PTC from a correct termination codon depends on splicing and translation, and it is the first and foremost step in human NMD. The molecular mechanism of this process remains elusive to date.
In the research proposed, I will undertake to elucidate the molecular basis of translation termination and induction of NMD. I will study complexes involved in human translation termination at a normal stop codon and involved in NMD. I will employ an array of innovative techniques including recombinant production of human protein complexes by the MultiBac system, mammalian in vitro translation, mass spectrometry for detecting relevant protein modifications, biophysical techniques, mutational analyses and RNA-interference experiments. Stable ribosomal complexes with termination factors and complexes of NMD factors will be used for structure determination by cryo-electron microscopy. State-of-the-art image processing will be applied to address the inherent heterogeneity of the complexes. Hybrid approaches will allow the combination of cryo-EM structures with existing high-resolution structures of factors involved for generation of quasi-atomic models thereby visualizing molecular mechanisms of NMD action. This interdisciplinary work will foster our understanding at a molecular level of a paramount step in mRNA quality control, which is a vital prerequisite for the development of new treatment strategies in NMD-related diseases.
Max ERC Funding
1 176 825 €
Duration
Start date: 2012-02-01, End date: 2016-11-30
Project acronym COMPNET
Project Dynamics and Self-organisation in Complex Cytoskeletal Networks
Researcher (PI) Andreas Bausch
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Country Germany
Call Details Starting Grant (StG), PE3, ERC-2011-StG_20101014
Summary The requirements on the eukaryotic cytoskeleton are not only of high complexity, but include demands that are actually contradictory in the first place: While the dynamic character of cytoskeletal structures is essential for the motility of cells, their ability for morphological reorganisations and cell division, the structural integrity of cells relies on the stability of cytoskeletal structures. From a biophysical point of view, this dynamic structure formation and stabilization stems from a self-organisation process that is tightly controlled by the simultaneous and competing function of a plethora of actin binding proteins (ABPs). To understand the self-organisation phenomena observed in the cytoskeleton it is therefore indispensable to first shed light on the functional role of ABPs and their underlying molecular mechanisms. Hereby development of reliable reconstituted model systems as has been proven by the great progress achieved in our understanding of individual crosslinking proteins that turn the cytoskeleton into a viscoelastic physical gel. The advantage of such reconstituted systems is that the biological complexity is decreased to an accessible level that the physical principles can be explored and identified.
It is the aim of the present proposal to successively increase the complexity in a well defined manner to further progress in understanding the functional units of a cell. On the way to a sound physical understanding of cellular self organizing principles, the planned major step comprises the incorporation of active processes like the active (de-)polymerisation of filaments and motor mediated active reorganisation and contraction. We plan to develop new tools and approaches to address how the different kinds of ABPs are interacting with each other and how the structure, dynamics and function of the cytoskeleton is locally governed by the competition and interplay between them.
Summary
The requirements on the eukaryotic cytoskeleton are not only of high complexity, but include demands that are actually contradictory in the first place: While the dynamic character of cytoskeletal structures is essential for the motility of cells, their ability for morphological reorganisations and cell division, the structural integrity of cells relies on the stability of cytoskeletal structures. From a biophysical point of view, this dynamic structure formation and stabilization stems from a self-organisation process that is tightly controlled by the simultaneous and competing function of a plethora of actin binding proteins (ABPs). To understand the self-organisation phenomena observed in the cytoskeleton it is therefore indispensable to first shed light on the functional role of ABPs and their underlying molecular mechanisms. Hereby development of reliable reconstituted model systems as has been proven by the great progress achieved in our understanding of individual crosslinking proteins that turn the cytoskeleton into a viscoelastic physical gel. The advantage of such reconstituted systems is that the biological complexity is decreased to an accessible level that the physical principles can be explored and identified.
It is the aim of the present proposal to successively increase the complexity in a well defined manner to further progress in understanding the functional units of a cell. On the way to a sound physical understanding of cellular self organizing principles, the planned major step comprises the incorporation of active processes like the active (de-)polymerisation of filaments and motor mediated active reorganisation and contraction. We plan to develop new tools and approaches to address how the different kinds of ABPs are interacting with each other and how the structure, dynamics and function of the cytoskeleton is locally governed by the competition and interplay between them.
Max ERC Funding
1 495 196 €
Duration
Start date: 2011-10-01, End date: 2012-03-31
Project acronym Counting conjectures
Project Counting conjectures and characters of almost simple groups
Researcher (PI) Gunter Malle
Host Institution (HI) TECHNISCHE UNIVERSITAT KAISERSLAUTERN
Country Germany
Call Details Advanced Grant (AdG), PE1, ERC-2011-ADG_20110209
Summary This proposal has two major goals: to understand the irreducible complex characters of the finite almost simple groups, and to apply this knowledge to prove two longstanding famous conjectures in the representation theory of finite groups: the McKay conjecture and the Alperin Weight Conjecture.
The first goal requires the study of the action of outer automorphisms of finite groups of Lie type on their irreducible characters and the solution of extension problems. The determination of the irreducible characters of all almost simple groups is a fundamental task of group theory.
For the second goal, we will build on the recent reductions (by the PI and others) of both conjectures to assertions on characters of finite simple groups. To prove these assertions, one needs to construct certain equivariant bijections with respect to outer automorphisms, which will involve the results from the first goal.
Furthermore, we propose to extend the reduction of the McKay conjecture to include several refinements, in particular the block-wise version and
congruences of character degrees.
The project will involve the interplay of methods from the theory of algebraic groups, character sheaves, block theory and modular character theory.
Summary
This proposal has two major goals: to understand the irreducible complex characters of the finite almost simple groups, and to apply this knowledge to prove two longstanding famous conjectures in the representation theory of finite groups: the McKay conjecture and the Alperin Weight Conjecture.
The first goal requires the study of the action of outer automorphisms of finite groups of Lie type on their irreducible characters and the solution of extension problems. The determination of the irreducible characters of all almost simple groups is a fundamental task of group theory.
For the second goal, we will build on the recent reductions (by the PI and others) of both conjectures to assertions on characters of finite simple groups. To prove these assertions, one needs to construct certain equivariant bijections with respect to outer automorphisms, which will involve the results from the first goal.
Furthermore, we propose to extend the reduction of the McKay conjecture to include several refinements, in particular the block-wise version and
congruences of character degrees.
The project will involve the interplay of methods from the theory of algebraic groups, character sheaves, block theory and modular character theory.
Max ERC Funding
1 444 200 €
Duration
Start date: 2012-04-01, End date: 2017-03-31
Project acronym CRYOTRANSLATION
Project High Resolution cryo-EM Analysis of Ribosome-associated Functions
Researcher (PI) Roland Beckmann
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Advanced Grant (AdG), LS1, ERC-2011-ADG_20110310
Summary "Translation of the genetically encoded information into polypeptides, protein biosynthesis, is a central function executed by ribosomes in all cells. In the case of membrane protein synthesis, integration into the membrane usually occurs co-translationally and requires a ribosome-associated translocon (SecYEG/Sec61). This highly coordinated process is poorly understood, since high-resolution structural information is lacking. Although single particle cryo-electron microscopy (cryo-EM) has given invaluable structural insights for such dynamic ribosomal complexes, the resolution is so far limited to 5-10 Å for asymmetrical particles. Thus, the mechanistic depth and reliability of interpretation has accordingly been limited.
Here, I propose to use single particle cryo-EM at improved, molecular resolution of 3-4 Å to study two fundamental ribosome-associated processes:
(i) co-translational integration of polytopic membrane proteins and
(ii) recycling of the eukaryotic ribosome.
First, we will visualize nascent polytopic membrane proteins inserting into the lipid bilayer via the bacterial ribosome-bound SecYEG translocon. Notably, the translocon will be embedded in a lipid environment provided by so-called nanodiscs. Second, we will visualize in a similar approach membrane protein insertion via the YidC insertase, the main alternative translocon. Third, as a novel research direction, we will determine the structure and function of eukaryotic ribosome recycling complexes involving the ABC-ATPase RLI.
The results will allow, together with functional biochemical data, an in-depth molecular structure-function analysis of these fundamental ribosome-associated processes. Moreover, reaching molecular resolution for asymmetrical particles by single particle cryo-EM will lift this technology to a level of analytical power approaching X-ray and NMR methods. ERC funding would allow for this highly challenging research to be conducted in an internationally competitive way in Europe."
Summary
"Translation of the genetically encoded information into polypeptides, protein biosynthesis, is a central function executed by ribosomes in all cells. In the case of membrane protein synthesis, integration into the membrane usually occurs co-translationally and requires a ribosome-associated translocon (SecYEG/Sec61). This highly coordinated process is poorly understood, since high-resolution structural information is lacking. Although single particle cryo-electron microscopy (cryo-EM) has given invaluable structural insights for such dynamic ribosomal complexes, the resolution is so far limited to 5-10 Å for asymmetrical particles. Thus, the mechanistic depth and reliability of interpretation has accordingly been limited.
Here, I propose to use single particle cryo-EM at improved, molecular resolution of 3-4 Å to study two fundamental ribosome-associated processes:
(i) co-translational integration of polytopic membrane proteins and
(ii) recycling of the eukaryotic ribosome.
First, we will visualize nascent polytopic membrane proteins inserting into the lipid bilayer via the bacterial ribosome-bound SecYEG translocon. Notably, the translocon will be embedded in a lipid environment provided by so-called nanodiscs. Second, we will visualize in a similar approach membrane protein insertion via the YidC insertase, the main alternative translocon. Third, as a novel research direction, we will determine the structure and function of eukaryotic ribosome recycling complexes involving the ABC-ATPase RLI.
The results will allow, together with functional biochemical data, an in-depth molecular structure-function analysis of these fundamental ribosome-associated processes. Moreover, reaching molecular resolution for asymmetrical particles by single particle cryo-EM will lift this technology to a level of analytical power approaching X-ray and NMR methods. ERC funding would allow for this highly challenging research to be conducted in an internationally competitive way in Europe."
Max ERC Funding
2 995 640 €
Duration
Start date: 2012-05-01, End date: 2017-04-30
