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FRIMEDBIO-Fri prosj.st. med.,helse,biol

ERC-MORTH Bicarbonate transporters in acid-base balance - A structural focus

Tildelt: kr 8,8 mill.

All mammalian cells use oxygen as an electron acceptor to run oxidative phosphorylation. Oxidative phosphorylation is connected to the citric acid cycle and thus to the complete breakdown of nutrients, ultimately generating carbon dioxide (CO2) as the fin al waste product. When CO2 is solubilised in water it forms carbonic acid (H2CO3); at physiological pH this ion is primarily found as the negatively charged bicarbonate ion (HCO3-). The fast conversion of CO2 to HCO3- is catalyzed by ubiquitous carbonic a nhydrases, which are found both in the cytoplasm and in the extracellular space. The bicarbonate ion accounts for more than 65 percent of the total buffering capacity in the body and is an important regulatory molecule for counteracting constant acidifica tion of the cytoplasm in most cell types. Bicarbonate transporters are grouped in two major classes, the solute carrier families 4 (SLC4) and 26 (SLC26), the latter of which is often associated with sulfate and oxalate transport as well. As of today, no c rystal structure is available for any bicarbonate/sulfate transporter. My aim is to unravel how bicarbonate is recognised and transported by the individual transporters at the atomic level by the use of X-ray crystallography. Our focus will include the N- terminal domains of the non-electrogenic chloride dependent bicarbonate transporters (NCBE), the independent bicarbonate transporters (NBCn1) and the electrogenic sodium dependent bicarbonate transporters (NBCe2).Structural characterization of the full le ngth prokaryotic bicarbonate/sulfate transporters of the SLC26 family will be pursue. The use of size exclusion chromatographic methods based on fluorescence will ensure a production pipeline that is able to produce enough membrane protein for a structura l study of this caliber. It will include a parallel biochemical characterisation approach in order to understand both the kinetics of bicarbonate transport and how to stabilise the bicarbonate transporters.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol