Descrizione del progetto
Conoscenza genomica della sopravvivenza all’aridità
In condizioni di aridità estrema, le proteine sono soggette a un’aggregazione irreversibile, fenomeno noto come essiccamento, che porta alla morte cellulare. Il progetto Desiccation Survival, finanziato dall’UE, sta studiando il ruolo delle proteine citosoliche termosolubili (CAHS, cytosolic abundant heat soluble) nella sopravvivenza dei micro-animali durante i periodi di aridità. Esse rappresentano una famiglia di proteine intrinsecamente disordinate che subiscono una transizione vetrosa per evitare lo spiegamento delle proteine intracellulari. I ricercatori esamineranno le caratteristiche della sequenza necessarie per questa attività protettiva e scopriranno nuove sequenze in grado di salvare le cellule dall’essiccamento. I risultati del progetto forniranno importanti conoscenze sul meccanismo d’azione delle proteine intrinsecamente disordinate e offriranno un paradigma per la progettazione di biomateriali innovativi.
Obiettivo
Desiccation is a form of stress wherein extremely dry conditions cause intracellular proteins to unfold and aggregate irreversibly, resulting in cell-death. How do cells and organisms survive desiccation is a fundamental question in biology. Cytosolic Abundant Heat Soluble (CAHS) proteins, a family of intrinsically disordered proteins (IDPs) in tardigrades (a phylum of micro-animals), have been shown to be important for their survival during long periods of dryness. Under desiccation condition, CAHS proteins undergo glass-transition and gelation to form vitrified solids that protect intracellular proteins from unfolding and aggregation. However, the features of CAHS proteins that confer protection are unknown. Here, I aim to unravel the sequence determinants of CAHS protein functions, by addressing 3 specific questions:
Aim 1: What are the sequence features that promote glass-transition and gelation in CAHS proteins?
Aim 2: Can we discover new sequences that can rescue cells from desiccation?
Aim 3: What is the sequence-to-function paradigm underlying IDP-mediated desiccation survival?
I will (i) perform computational analysis of existing CAHS proteins to extract their sequence features to design a library for adequate sampling of the sequence space; (ii) screen the library with a high-throughput survival-based assay and validate the hits both in vitro and in vivo; (iii) analyse the results with machine learning algorithms to generate characteristic sequence features underlying protective glass-transition. The learned features will be tested by rationally designing and screening a new sequence library for desiccation survival. This project will provide fundamental sequence-level understanding of how IDPs promote stress response, specifically via glass-transition during desiccation. Moreover, the materials and pipeline generated and the findings of this study will aid in engineering functional biomaterials.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
SN2 1FL Swindon
Regno Unito