Description du projet
Structure, dynamique et réglementation des transporteurs de solutés
Les transporteurs de solutés (SL) constituent une famille de plus de 300 protéines liées aux membranes qui facilitent le transport d’une variété de substrats à travers les membranes biologiques, allant de la rétention des nutriments à l’absorption de médicaments. Les activités de nombreux transporteurs de SL sont régulées de manière allostérique par la liaison de facteurs accessoires, tels que les hormones, et la compréhension des mécanismes sous‑jacents est essentielle pour la conception de futurs médicaments. Le projet EXCHANGE, financé par l’UE, utilise un système modèle de la famille des SL, appelé échangeurs sodium/proton (NHE), qui échangent du sodium contre des protons à travers les membranes. Le projet vise à déterminer la structure, la dynamique et la régulation allostérique des NHE afin de mettre en évidence d’importantes connaissances mécanistes pertinentes non seulement pour les NHE, mais aussi pour de nombreux types de transporteurs de SL.
Objectif
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.
Champ scientifique
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health sciencesbasic medicinemedicinal chemistry
- natural scienceschemical sciencesinorganic chemistryalkali metals
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
10691 Stockholm
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