TRIM

Structure-Function Studies of the TRIM Family of Ubiquitin E3 Ligases

Coordinatore	THE HEBREW UNIVERSITY OF JERUSALEM.    more  Organization address address: GIVAT RAM CAMPUS city: JERUSALEM postcode: 91904 contact info Titolo: Ms. Nome: Hani Cognome: Ben-Yehuda Email: send email Telefono: +972 2 6586676 Fax: +972 72 2447007
Nazionalità Coordinatore	Israel [IL]
Totale costo	100˙000 €
EC contributo	100˙000 €
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-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-06-01   -   2018-05-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	THE HEBREW UNIVERSITY OF JERUSALEM.  Organization address address: GIVAT RAM CAMPUS city: JERUSALEM postcode: 91904 contact info Titolo: Ms. Nome: Hani Cognome: Ben-Yehuda Email: send email Telefono: +972 2 6586676 Fax: +972 72 2447007	IL (JERUSALEM)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Ubiquitin E3 enzymes participate in the last step of a three-enzyme cascade, where they transfer ubiquitin from E2 enzymes to substrates, therefore are responsible to bring the right substrate to the right E2 enzyme. The tripartite motif (TRIM) family of ubiquitin E3 ligases includes 70 members that are involved in cellular processes such as immune signaling, transcriptional regulation and apoptosis. Defects in TRIM E3 ligase activity have been linked to cancer and developmental and genetic diseases. Despite TRIM vital roles, important aspects of their mechanism as E3 ligases remain unknown mainly due to their multi-domain architecture, their ability to self-associate into dimers and higher order complexes, and their ability to serve as E3 ligases not only for ubiquitin but also for ubiquitin-like proteins. We will pursue our interest in the molecular mechanism of TRIM E3 activity by working on TRIM25 that possesses dual E3 activity for ubiquitin and ubiquitin-like protein ISG15. We will determine the molecular mechanism of TRIM25 E3 activity using molecular biology, cell biology, crystallography and biochemistry. Specifically, we will map the contribution of TRIM25 different domains and the oligomineric state to its E3 activity. Then, together with crystal structures of TRIM25 with its cognate E2, UBCH8, charged with ubiquitin or ISG15, we will provide structural insight on how TRIM25 works in concert with UBCH8 and possesses dual E3 activity. In addition, we will determine how TRIM25 interacts with its substrate, 14-3-3σ, and whether the oligomeric state is important for substrate binding. Since 14-3-3σ undergoes ubiquitination and ISGylation by TRIM25 we will investigate the potential crosstalk between modifications. Specifically, we will test for the formation of mixed ubiquitin-ISG15 chains. Our work will provide mechanistic details on TRIM E3 ligase activity as well as critical data for future research on TRIM proteins as targets for therapeutic drug design.'