DC10

Background: BARS, a member of the C-terminal-binding protein (CtBP) family, is a dual function protein acting as transcription regulator in the nucleus in its dimeric/tetrameric NADH-bound form, and as membrane-fission protein (in its AcylCoA-bound monomeric form) in intracellular traffic steps such as formation of post-Golgi tubular/pleiomorphic carriers, macropinosomes, COPI-dependent transport vesicles and partitioning of the Golgi complex during mitosis. BARS also plays a role as a metabolic/redox sensor that is activated by NADH-binding. Increase in NADH level inhibits the monomeric fission-competent form of BARS and, thus, intracellular membrane transport. This mechanism supports cellular energy homeostasis by reducing energy consumption.

Objectives: (1) In vitro studies to evaluate NAD-NADH-AcylCoA binding constants related to BARS structural transition (chromatography and cryoTEM studies). (2) Modulate the cellular concentrations of the BARS-ligands: verify/validate structural transition in intact cells 3) use appropriate cell systems, as developed in our lab, to analyze the interplay between NAD and AcylCoA metabolism and BARS functions 4) verify the activity of small molecules (already available from a virtual screening campaign) to modulate BARS activity in pathological conditions (methods available in the lab)