Protein quality control mechanism inside the cell
Improper folding of proteins has severe pathological consequences, e.g. amyloidosis, such as Alzheimer and Creutzfeldt-Jakob disease; lung diseases, such as cystic fibrosis or hereditary emphysema; diabetes, in which misfolded proteins disrupt carbohydrate metabolism, or even accumulate in the ER; liver diseases, in which proteins needed in signaling or enzyme regulation are retained in the ER etc.
The most direct way for a cell to avoid the accumulation of damaged proteins is to avoid creating flawed proteins (for further reading: Weissman JS and colleagues, Cell. 2014,157(1):52-64). It does so by recognizing and controlling the errors as the polypeptides are being synthesized on the ribosome. Despite of the presence of such quality control mechanisms, we still don’t know why they are apparently ineffective in case of diseases.
A key step for the therapeutic intervention of these diseases would be to improve our present understanding of the protein quality control mechanism. Inside the cell, this quality control operates mainly at two stages in the life cycle of individual proteins – first, during the biogenesis of proteins on the ribosomes and second, when proteins reside inside the cellular organelles (like, Endoplasmic Reticulum (ER), Golgi etc.) or in cytosol. Either one of these quality control measures, or all of them, could be affected under disease conditions where non-functional protein structures are formed. In this project, our goal is to study the quality control mechanism, during the biogenesis of proteins. It has been proposed, that the most direct way for a cell to avoid accumulation of cytotoxic protein structures, is to merely avoid their formation.
We aim to investigate:
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How functional protein structures are protected during their biogenesis?
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How protein biosynthetic machinery is functionally linked to the chaperone network of cell?
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What role ribosome associated protein quality control machinery plays to produce cytotoxic protein structures?
We use a range of biochemical and biophysical measurements, to address the questions, which are difficult to study in cell-based experiments. Techniques include, but not limited to, the steady state measurements as well as the fast kinetic measurements using stopped flow, quench flow etc. We validate our in vitro observation inside the cell.