RHOMBOID SUBSTRATES

"Substrate specificity, mechanism and biological roles of rhomboid intramembrane proteases."

Coordinatore	"USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I."    more  Organization address address: FLEMINGOVO NAM. 542/2 city: PRAHA 6 postcode: 16610 contact info Titolo: Ms. Nome: Jitka Cognome: Silerova Email: send email Telefono: 420220000000
Nazionalità Coordinatore	Czech Republic [CZ]
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-2011-CIG
Funding Scheme	MC-CIG
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-03-01   -   2017-02-28

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	"USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I."  Organization address address: FLEMINGOVO NAM. 542/2 city: PRAHA 6 postcode: 16610 contact info Titolo: Ms. Nome: Jitka Cognome: Silerova Email: send email Telefono: 420220000000	CZ (PRAHA 6)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Rhomboids are widely conserved intramembrane proteases. They are known to control important biological processes in model insect, worm, yeast and protozoan species, but their functions in most organisms including mammals and bacteria are unknown. The key to the understanding of rhomboid functions are their natural substrates, but it has been unclear how these are selected and recognized and methods for substrate identification have been lacking, which is limiting progress in the field.

The core of this proposal aims to discover the biological roles of highly conserved rhomboids by identifying their natural substrates using a combination of advanced substrate specificity analysis, quantitative proteomics and genetics. I will initially focus on representative conserved bacterial rhomboids and identify their substrate repertoire using an in vitro biochemical screen. Subsequent biochemical and genetic analysis in vivo will reveal the biology of the substrates and rhomboids and indicate functions of their orthologues in pathogens. Enzymatic analysis of the identified substrates will elucidate rhomboid specificity and help us solve the three dimensional structure of a rhomboid substrate complex. In a complementary approach, I will use quantitative proteomics to identify substrate repertoire and elucidate substrate specificity of mammalian endoplasmic reticulum (ER) localised rhomboid RHBDL4, which will enable me to understand its biological role in ER-stress-induced cell death, indicated by preliminary experiments.

This project will yield novel biological insights, provide a platform for rhomboid substrate discovery applicable to other biological contexts including pathogens, and provide a deep mechanistic and structural insight into rhomboid protease function, which will help us design new effective rhomboid inhibitors that are needed as experimental tools and have medical potential.'