Descrizione del progetto
Un approccio in silico alla dissezione delle strutture di membrana
I lipidi vengono sintetizzati principalmente nel reticolo endoplasmatico e vengono trasportati alle membrane degli organelli tramite vescicole. Le evidenze emergenti indicano che il trasporto di lipidi tra gli organelli può avvenire anche attraverso vie non vescicolari che impiegano proteine di trasporto dei lipidi. Questo processo consente inoltre alle cellule di modificare la composizione lipidica delle loro membrane a seconda delle condizioni. Il progetto MCS-MD, finanziato dall’UE, si propone di delineare la struttura dei siti di contatto della membrana (MCS, membrane contact sites) nei quali avviene questo trasporto di lipidi. I ricercatori caratterizzeranno le proteine MCS e il meccanismo con cui assistono il trasporto dei lipidi e altri processi.
Obiettivo
The goal of this project is to obtain an atomistic structural and dynamical characterization of the inner workings of membrane contact sites (MCS) between intracellular organelles, in order to understand how molecular processes such as non-vesicular lipid transport at MCS might modulate lipid homeostatic processes at the whole-cell scale.
Investigation of the mechanisms taking place at MCS has emerged as a central topic in cellular biology in the last few years, and it has led to a large amount of novel cellular, biochemical and structural data that has drastically revolutionized our general understanding of lipid homeostasis in the cell. Yet, due to limitations of experimental methods, a high-resolution understanding of how MCS proteins work is still limited, and the specific molecular details of these mechanisms are still under intense debate, and especially concerning the specificity of lipid transport or the discrimination between lipid sensing and lipid transport.
To understand these processes with unprecedented molecular detail, I will develop high-throughput protocols based on atomistic and coarse-grain molecular dynamics simulations that leverage and take advantage of all the available, yet often scattered, experimental data. With these approaches, that have not been used so far to investigate MCS because of the extreme complexity of these cellular machineries, I will obtain a detailed understanding of key molecular processes taking place at MCS, including the specificity of membrane binding, the mechanism of lipid uptake and release, the influence of confinement on protein activity, and the role of membrane lipid composition in the regulation of lipid transport.
This approach will drive forward our perception of the limits of structure-based in-silico methods, and it will contribute to our mechanistic understanding of key cellular biology processes by providing new quantitative results that are beyond the current possibilities of experimental approaches.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
1700 Fribourg
Svizzera