Projektbeschreibung
Struktur, Dynamik und Regulierung von SLC-Transportern
Zu den SLC-Transportern (Solute Carrier) gehören mehr als 300 membrangebundene Proteine, die zahlreiche Substrate in den biologischen Membranen transportieren. Das reicht von der Aufnahme von Nährstoffen bis zur Absorption von Wirkstoffen. Die Aktivitäten vieler SLC-Transporter werden über die Bindung zusätzlicher Faktoren, wie Hormone, allosterisch reguliert. Damit auch in Zukunft Wirkstoffe entwickelt werden können, ist eine Klärung der zugrunde liegenden Mechanismen notwendig. Im Rahmen des EU-finanzierten Projekts EXCHANGE kommt ein Modellsystem aus der SLC-Familie zum Einsatz: die Natrium-Protonen-Austauscher. Diese tauschen in den Membranen Natrium gegen Protonen aus. Das Projektteam möchte die Struktur, Dynamik und allosterische Regulierung von Natrium-Protonen-Austauschern untersuchen und so wichtige mechanistische Einblicke gewinnen, die nicht nur für sie, sondern auch für zahlreiche SLC-Transporter von Bedeutung sind.
Ziel
Solute Carrier (SLC) transporters mediate the translocation of substrates across membranes and after GPCRs represent the second-largest fraction of the human membrane proteome. SLC transporters are critical to cell homeostasis, which is reflected in the fact that more than a quarter is associated with Mendelian disease. Despite a few exceptions, however, they have been under-utilized as drug targets and most of the mechanistic understanding has been derived from bacterial homologues of these medically important proteins. In addition to subtle differences, bacterial homologues will not enable us to establish how the activities of many SLC transporters are allosterically regulated through the binding of accessory factors, e.g. hormones, to their non-membranous globular domains. Understanding the mechanisms by which their activities can be allosterically regulated through these complex and dynamic assembles is critical to human physiology and important for future drug design.
Our model system is a family of transporters known as sodium/proton exchangers (NHEs), which exchange sodium for protons across membranes to aid many fundamental processes in the cell. NHEs are important to the cell cycle, cell proliferation, cell migration and vesicle trafficking and are associated with a wide-spectrum of diseases. Their diverse portfolio is connected to the importance of pH homeostasis, and the binding of many different factors to a large, globular cytosolic domain exquisitely regulates them. To date, we have no structural information for any of the NHE’s, functional assays in liposomes are lacking, and many interaction partners are yet to be validated by in vitro studies. Determining the structure, dynamics, and allosteric regulation of NHEs will be an enormous challenge. However, we envisage that by achieving our objectives, we will reveal important mechanistic insights relevant not just to NHEs, but to many types of SLC transporters.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health sciencesbasic medicinemedicinal chemistry
- natural scienceschemical sciencesinorganic chemistryalkali metals
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
10691 Stockholm
Schweden