Descrizione del progetto
Strutture, dinamiche e regolazione dei trasportatori dei portatori di soluto
Le proteine di trasporto del gruppo portatore di soluti (SLC, Solute Carrier) rappresentano una famiglia di oltre 300 proteine legate alla membrana che agevolano il trasporto di vari substrati attraverso le membrane biologiche, che vanno dall’assimilazione delle sostanze nutritive all’assorbimento dei farmaci. Le attività di molti trasportatori di SLC sono regolate allostericamente mediante il legame di fattori accessori, quali gli ormoni, e la comprensione dei meccanismi sottostanti è fondamentale per la futura progettazione di farmaci. Il progetto EXCHANGE, finanziato dall’UE, si avvale di un sistema modello proveniente dalla famiglia di SLC nota come scambiatori sodio-protone (NHE, Sodium/Proton Exchangers) che scambia sodio per protoni attraverso le membrane. Il progetto mira a stabilire la struttura, le dinamiche e la regolazione allosterica degli NHE per svelare importanti spunti meccanicistici, che sono di rilievo non solo per i suddetti scambiatori ma anche per numerosi tipi di trasportatori di SLC.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
10691 Stockholm
Svezia