Projektbeschreibung
Ein In-silico-Ansatz zur Entschlüsselung von Membranstrukturen
Lipide werden hauptsächlich im endoplasmatischen Retikulum synthetisiert und über Vesikel an die Membran von Organellen transportiert. Neue Erkenntnisse deuten an, dass der Transport von Lipiden zwischen Organellen auch ohne vesikuläre Pfade möglich ist, mit Transportproteinen für Lipide. So können Zellen zudem die Lipidzusammensetzung ihrer Membran situationsbedingt verändern. Das EU-finanzierte Projekt MCS-MD verfolgt das Ziel, die Struktur von Membrankontaktstellen zu beschreiben, an denen solche Lipidtransporte stattfinden. Die Forschenden werden die Proteine an den Membrankontaktstellen sowie die Mechanismen zur Unterstützung des Lipidtransports und andere Prozesse charakterisieren.
Ziel
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.
Wissenschaftliches Gebiet
Not validated
Not validated
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
1700 Fribourg
Schweiz