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Zawartość zarchiwizowana w dniu 2024-06-18

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

Cel

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.

Zaproszenie do składania wniosków

FP7-PEOPLE-2011-CIG
Zobacz inne projekty w ramach tego zaproszenia

Koordynator

USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I.
Wkład UE
€ 100 000,00
Adres
FLEMINGOVO NAM. 542/2
16610 Praha 6
Czechy

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Region
Česko Praha Hlavní město Praha
Rodzaj działalności
Research Organisations
Kontakt administracyjny
Jitka Silerova (Ms.)
Linki
Koszt całkowity
Brak danych