Project description
Abnormal kinase activity in Tau biomolecular condensates
Over-phosphorylation of Tau – a protein that stabilises neuron structure – is a hallmark of Alzheimer’s disease. Evidence suggests that Tau undergoes biomolecular condensation in Alzheimer’s disease and that these condensates may be recognisable sites for kinases, the enzymes responsible for phosphorylation. The molecular mechanisms of kinase activity in condensates are unknown. With the support of the Marie Skłodowska-Curie Actions programme, the KinCond project aims to shed light to those mechanisms with a focus on the microtubule affinity-regulating kinase MARK2 involved in the abnormal phosphorylation of Tau. The project will study the specificity and selectivity of MARK2 in Tau condensates, its conformational dynamics and changes in its conformation during biomolecular condensation using experimental methods and simulations.
Objective
Protein phosphorylation, mediated by kinases, plays a pivotal role in cellular regulation, with kinase dysregulation strongly associated with diseases like cancer, inflammation, and neurodegenerative disorders. Alzheimer's disease (AD) represents a significant global health challenge as the population ages at an accelerating pace. A key pathological feature of AD is the accumulation of hyperphosphorylated Tau, which disrupts normal neuronal function. Emerging evidence suggests that Tau undergoes liquid-liquid phase separation (LLPS), potentially linking AD and biomolecular condensation. Moreover, recent findings propose that LLPS intricately manages kinase signalling, creating condensed-phase structures (biomolecular condensates) that serve as recognizable sites for kinases. However, molecular mechanisms governing kinase behaviour within condensates are poorly understood. The central hypothesis of KinCond project is that the conformational landscape of protein kinases undergoes significant remodelling within biomolecular condensates, controlling substrate selectivity and specificity. This project focuses on the microtubule affinity-regulating kinase MARK2, a central player in the abnormal phosphorylation of Tau. KinCond is meticulously structured into three work packages: (1) investigating the specificity and reaction kinetics of MARK2 within Tau condensates, (2) deciphering the conformational landscape of MARK2 through advanced nuclear magnetic resonance methods and molecular dynamics simulations and (3) analyse the effect of biomolecular condensation on the conformational landscape of MARK2. The outcomes of KinCond are expected to provide crucial insights into the behaviour of protein kinases within biomolecular condensates, shedding much-needed light on the mechanisms of Tau phosphorylation in AD. Furthermore, the atomic-detail information obtained has the potential to open new avenues for the development of enhanced drugs targeting protein kinases.
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Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2023-PF-01
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53127 Bonn
Germany
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