Project description
Structure, dynamics and regulation of solute carrier transporters
Solute carrier (SLC) transporters are a family of more than 300 membrane-bound proteins that facilitate the transport of a variety of substrates across biological membranes, ranging from the uptake of nutrients to the absorption of drugs. The activities of many SLC transporters are allosterically regulated through the binding of accessory factors, such as hormones, and understanding the underlying mechanisms is critical for future drug design. The EU-funded EXCHANGE project uses a model system from the SLC family known as sodium/proton exchangers (NHEs) which exchange sodium for protons across membranes. The project aims to determine the structure, dynamics and allosteric regulation of NHEs to reveal important mechanistic insights relevant not just to NHEs, but to numerous types of SLC transporters.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
10691 Stockholm
Sweden