Objective
14-3-3 proteins, found in all eukaryotic cells, are known to be important in cell-cycle regulation, apoptosis, and regulation of gene expression. They are also associated with oncogenic and neurodegenerative amyloid diseases. 14-3-3 proteins are active as homo- or heterodimers and bind more than 300 diverse target phosphoproteins, thereby forcing conformational changes or/and stabilizing active conformations in their target proteins. To date, no crystal structure is known for a 14-3-3 dimer in complex with a doubly phosphorylated target protein; this prevents a full understanding of the 14-3-3 molecular mechanism. I propose a computational approach to model the function of 14-3-3s on three of its target ligands: serotonin N-acetyltransferase (AANAT), tyrosine hydroxylase, and tryptophan hydroxylase. This approach will combine restrained molecular dynamics simulation for phosphorylated residues with the novel Hamiltonian replica exchange using soft-core interactions developed by myself and Dr. Oostenbrink. The obtained structure for 14-3-3/AANAT will be compared with the available crystal structure of AANAT in its active form. Computationally predicted structures of doubly phosphorylated tyrosine hydroxylase or doubly phophorylated tryptophan hydroxylase in complex with a 14-3-3 dimer will be verified by comparison with several fingerprint-type NMR spectra measured for each complex during the proposed project. The proposed approach will have general applicability to most doubly phosphorylated 14-3-3 protein ligands. The research proposed here will not only deepen our understanding of 14-3-3 function, but will also enhance our knowledge of essential basic mechanisms with respect to key regulatory proteins.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- engineering and technology materials engineering crystals
- natural sciences biological sciences biochemistry biomolecules proteins
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-IOF-2008
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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.
Coordinator
601 77 Brno
Czechia
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.