Project acronym Phosphoprocessors
Project Biological signal processing via multisite phosphorylation networks
Researcher (PI) Mart Loog
Host Institution (HI) TARTU ULIKOOL
Call Details Consolidator Grant (CoG), LS1, ERC-2014-CoG
Summary Multisite phosphorylation of proteins is a powerful signal processing mechanism playing crucial roles in cell division and differentiation as well as in disease. Our goal in this application is to elucidate the molecular basis of this important mechanism. We recently demonstrated a novel phenomenon of multisite phosphorylation in cell cycle regulation. We showed that cyclin-dependent kinase (CDK)-dependent multisite phosphorylation of a crucial substrate is performed semiprocessively in the N-to-C terminal direction along the disordered protein. The process is controlled by key parameters including the distance between phosphorylation sites, the distribution of serines and threonines in sites, and the position of docking motifs. According to our model, linear patterns of phosphorylation networks along the disordered protein segments determine the net phosphorylation rate of the protein. This concept provides a new interpretation of CDK signal processing, and it can explain how the temporal order of cell cycle events is achieved. The goals of this study are: 1) We will seek proof of the model by rewiring the patterns of budding yeast Cdk1 multisite networks according to the rules we have identified, so to change the order of cell cycle events. Next, we will restore the order by alternative wiring of the same switches; 2) To apply the proposed model in the context of different kinases and complex substrate arrangements, we will study the Cdk1-dependent multisite phosphorylation of kinetochore components, to understand the phospho-regulation of kinetochore formation, microtubule attachment and error correction; 3) We will apply multisite phosphorylation to design circuits for synthetic biology. A toolbox of synthetic parts based on multisite phosphorylation would revolutionize the field since the fast time scales and wide combinatorial possibilities.
Summary
Multisite phosphorylation of proteins is a powerful signal processing mechanism playing crucial roles in cell division and differentiation as well as in disease. Our goal in this application is to elucidate the molecular basis of this important mechanism. We recently demonstrated a novel phenomenon of multisite phosphorylation in cell cycle regulation. We showed that cyclin-dependent kinase (CDK)-dependent multisite phosphorylation of a crucial substrate is performed semiprocessively in the N-to-C terminal direction along the disordered protein. The process is controlled by key parameters including the distance between phosphorylation sites, the distribution of serines and threonines in sites, and the position of docking motifs. According to our model, linear patterns of phosphorylation networks along the disordered protein segments determine the net phosphorylation rate of the protein. This concept provides a new interpretation of CDK signal processing, and it can explain how the temporal order of cell cycle events is achieved. The goals of this study are: 1) We will seek proof of the model by rewiring the patterns of budding yeast Cdk1 multisite networks according to the rules we have identified, so to change the order of cell cycle events. Next, we will restore the order by alternative wiring of the same switches; 2) To apply the proposed model in the context of different kinases and complex substrate arrangements, we will study the Cdk1-dependent multisite phosphorylation of kinetochore components, to understand the phospho-regulation of kinetochore formation, microtubule attachment and error correction; 3) We will apply multisite phosphorylation to design circuits for synthetic biology. A toolbox of synthetic parts based on multisite phosphorylation would revolutionize the field since the fast time scales and wide combinatorial possibilities.
Max ERC Funding
1 999 289 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym QGP tomography
Project A novel Quark-Gluon Plasma tomography tool: from jet quenching to exploring the extreme medium properties
Researcher (PI) Magdalena DJORDJEVIC
Host Institution (HI) INSTITUT ZA FIZIKU
Call Details Consolidator Grant (CoG), PE2, ERC-2016-COG
Summary Quark-Gluon Plasma (QGP) is a primordial state of matter, which consists of interacting free quarks and gluons. QGP likely existed immediately after the Big-Bang, and this extreme form of matter is today created in Little Bangs, which are ultra-relativistic collisions of heavy nuclei at the LHC and RHIC experiments. Based on the deconfinement ideas, a gas-like behaviour of QGP was anticipated. Unexpectedly, predictions of relativistic hydrodynamics - applicable to low momentum hadron data - indicated that QGP behaves as nearly perfect fluid, thus bringing exciting connections between the hottest (QGP) and the coldest (perfect Fermi gas) matter on Earth. However, predictions of hydrodynamical simulations are often weakly sensitive to changes of the bulk QGP parameters. In particular, even a large increase of viscosity not far from the phase transition does not notably change the low momentum predictions; in addition, the origin of the surprisingly low viscosity remains unclear. To understand the QGP properties, and to challenge the perfect fluid paradigm, we will develop a novel precision tomographic tool based on: i) state of the art, no free parameters, energy loss model of high momentum parton interactions with evolving QGP, ii) simulations of QGP evolution, in which the medium parameters will be systematically varied, and the resulting temperature profiles used as inputs for the energy loss model. In a substantially novel approach, this will allow using the data of rare high momentum particles to constrain the properties of the bulk medium. We will use this tool to: i) test our “soft-to-hard” medium hypothesis, i.e. if the bulk behaves as a nearly perfect fluid near critical temperature Tc, and as a weakly coupled system at higher temperatures, ii) map “soft-to-hard” boundary for QGP, iii) understand the origin of the low viscosity near Tc, and iv) test if QGP is formed in small (p+p or p(d)+A) systems.
Summary
Quark-Gluon Plasma (QGP) is a primordial state of matter, which consists of interacting free quarks and gluons. QGP likely existed immediately after the Big-Bang, and this extreme form of matter is today created in Little Bangs, which are ultra-relativistic collisions of heavy nuclei at the LHC and RHIC experiments. Based on the deconfinement ideas, a gas-like behaviour of QGP was anticipated. Unexpectedly, predictions of relativistic hydrodynamics - applicable to low momentum hadron data - indicated that QGP behaves as nearly perfect fluid, thus bringing exciting connections between the hottest (QGP) and the coldest (perfect Fermi gas) matter on Earth. However, predictions of hydrodynamical simulations are often weakly sensitive to changes of the bulk QGP parameters. In particular, even a large increase of viscosity not far from the phase transition does not notably change the low momentum predictions; in addition, the origin of the surprisingly low viscosity remains unclear. To understand the QGP properties, and to challenge the perfect fluid paradigm, we will develop a novel precision tomographic tool based on: i) state of the art, no free parameters, energy loss model of high momentum parton interactions with evolving QGP, ii) simulations of QGP evolution, in which the medium parameters will be systematically varied, and the resulting temperature profiles used as inputs for the energy loss model. In a substantially novel approach, this will allow using the data of rare high momentum particles to constrain the properties of the bulk medium. We will use this tool to: i) test our “soft-to-hard” medium hypothesis, i.e. if the bulk behaves as a nearly perfect fluid near critical temperature Tc, and as a weakly coupled system at higher temperatures, ii) map “soft-to-hard” boundary for QGP, iii) understand the origin of the low viscosity near Tc, and iv) test if QGP is formed in small (p+p or p(d)+A) systems.
Max ERC Funding
1 356 000 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
