Objective
Ubiquitination is a reversible post-translational modification (PTM) regulating diverse cellular functions including cell cycle, apoptosis, gene expression, inflammation and DNA repair. Ubiquitination results in the tagging of proteins with either monoubiquitin or polyubiquitin chains of different linkages that are structurally distinct. Given that protein ubiquitination is involved in so many cellular processes, it needs to be under very tight regulation. Protein ubiquitination is reversed by deubiquitinases (DUBs), which are specialized proteases that cleave the isopeptide linkage between ubiquitin molecules in chains or between ubiquitin and protein substrates. The objective of this study is to understand how substrate specificity is determined and in particular, how function of the A20-family of ovarian tumour (OTU) DUBs is regulated. I will crystallize the catalytic domains of OTU family DUBs involved in cell signalling, to understand their ubiquitin chain linkage specificity. I intend to establish how the interacting scaffolding proteins of A20-like DUBs, such as ABIN and TAX1BP1, mediate substrate targeting and specificity, and allosterically regulate enzyme activity. I shall express full-length protein complexes of A20 and Cezanne together with their interacting proteins using multi-gene baculovirus and mammalian systems. I will use X-ray crystallography and electron microscopy to understand the structure and conformational changes regulating DUB complex activation. The structural insights obtained will be used to understand oncogenic DUB mutants, and establish how DUB dysregulation leads to tumorigenesis. Lastly, I will analyze how reversible oxidation regulates DUBs during signalling. The proposed structural and biochemical characterisation of the multi-subunit protein complexes of DUBs will help define the molecular details of allosteric mechanisms governing A20-like DUBs and provide the basis for design of pharmaceutical modulators of DUB activity.
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: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences cell biology cell signaling
- natural sciences chemical sciences electrochemistry electrolysis
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- natural sciences physical sciences optics microscopy electron microscopy
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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.
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
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2009-IEF
See other projects for this call
Funding Scheme
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.
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
W1B 1AL LONDON
United Kingdom
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.