BISSOT'D

Biochemical and Structural characterization of signal transduction by OTU family of Deubiquitinases

Coordinatore	MEDICAL RESEARCH COUNCIL    more  Organization address address: NORTH STAR AVENUE POLARIS HOUSE city: SWINDON postcode: SN2 1FL contact info Titolo: Ms. Nome: Elizabeth Cognome: Cutler Email: send email Telefono: +44 (0) 1223 402357 Fax: +44 (0) 1223 412 515
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	180˙103 €
EC contributo	180˙103 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2009-IEF
Funding Scheme	MC-IEF
Anno di inizio	2010
Periodo (anno-mese-giorno)	2010-04-01   -   2012-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	MEDICAL RESEARCH COUNCIL  Organization address address: NORTH STAR AVENUE POLARIS HOUSE city: SWINDON postcode: SN2 1FL contact info Titolo: Ms. Nome: Elizabeth Cognome: Cutler Email: send email Telefono: +44 (0) 1223 402357 Fax: +44 (0) 1223 412 515	UK (SWINDON)	coordinator	180˙103.20

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 Obiettivo del progetto (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.'