Descripción del proyecto
Estructura, dinámica y regulación de los transportadores de portadores de solutos
Los transportadores de portadores solutos (SLC, por sus siglas en inglés) son una familia de más de trescientas proteínas ligadas a membrana que facilitan el transporte de diversos sustratos entre membranas biológicas, que van desde la absorción de nutrientes a la de fármacos. Las actividades de muchos transportadores SLC se regulan de forma alostérica a través de la unión de factores accesorios, como las hormonas, y la comprensión de los mecanismos subyacentes a este proceso es fundamental para el diseño de fármacos futuros. El proyecto financiado con fondos europeos EXCHANGE utiliza un sistema modelo de la familia de SLC conocida como intercambiadores de sodio/protones que intercambian sodio por protones entre membranas. En el proyecto se busca determinar la estructura, dinámica y regulación alostérica de los intercambiadores de sodio/protones para revelar información mecanicista importante no solo sobre estos intercambiadores, sino también para numerosos tipos de transportadores SLC.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
10691 Stockholm
Suecia