Project Details
Projekt
Transport mechanisms and cellular functions of SLC26A11
Subject Area
Anatomy and Physiology
Term
from 2020 to 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426950122
SLC26A11 is a member of the SLC26 family expressed in brain, kidney, gastrointestinal epithelia, chondrocytes and high endothelial venules. Thus far, conflicting data about transport mechanisms, subcellular distribution and cellular functions have been published, leaving these important features of SLC26A11 insufficiently understood. In the first funding period, a combination of cellular electrophysiology (by P4) and radiotracer flux measurements (by P1) demonstrated a dual function behavior of SLC26A11 as electroneutral H+/SO42-:Cl- exchanger and a Cl- channel. These findings, together with the recent determination of the SLC26A11 structure, have opened the way to study transport functions of this transporter with a combination of computational and experimental techniques. We will use multiscale quantum mechanics/molecular mechanics simulations to study the molecular basis of sulfate/chloride/oxalate selectivity and pinpoint residues responsible for proton/hydroxide transfer. Residues predicted to be functionally important by simulations will be scrutinized in experiments, using site-directed mutagenesis, heterologous expression, patch clamp electrophysiology and fluorescence spectroscopy. In heterologous expression systems, SLC26A11 almost exclusively localizes to the lysosome. To understand cellular functions of the unique anion transport by SLC26A11 in these cell compartments, we will study lysosomal ion concentrations and changes of lysosomal ion concentration upon modification of lysosomal transporter. To test for the presence of SLC26A11 in the plasma membrane of differentiated cells, we will study the subcellular distribution of SLC26A11 in mouse brain, kidney and high endothelial venules using immunohistochemistry.
DFG Programme
Research Units
