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Biological signal processing via multisite phosphorylation networks

Project description

Increasing our understanding of biological signal processing

Biological signal processing plays a vital role in the functioning of various living organisms, particularly in crucial processes like cell division and combating diseases that affect the organism. Therefore, gaining a deeper understanding of and enhancing control over this phenomenon hold immense significance for the future of relevant sectors and industries. The ERC-funded Phosphoprocessors project aims to build upon its team members’ previous research on multi-site phosphorylation and delve further into the intricate workings of cyclin-dependent kinases. By conducting rigorous testing, their ultimate goal is to attain a more comprehensive and explainable understanding of the sequential occurrence of cell cycle events.

Objective

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.

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Coordinator

TARTU ULIKOOL
Net EU contribution
€ 1 999 288,67
Address
Ulikooli 18
51005 Tartu
Estonia

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Region
Eesti Eesti Lõuna-Eesti
Activity type
Higher or Secondary Education Establishments
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Other funding
€ 0,00

Beneficiaries (1)