Hsp70 in eukaryotic protein folding and quality control

Research is primarily focused on understanding the mechanisms by which the eukaryotic cell maintains all of its proteins folded and functional. Breakdown of these mechanisms has severe consequences for the cell and results in the accumulation of toxic misfolded and aggregated proteins. Strikingly, protein aggregates are found in the brains of individuals with neurodegenerative disease, e.g. Alzheimer’s and Parkinson’s. Understanding the molecular mechanisms that maintain cellular proteins folded and functional is a fundamental challenge in biological sciences and is crucial in the battle against disease.

Experiments are based on the cytosolic heat-shock protein 70 kDa (Hsp70) class in budding yeast (Saccharomyces cerevisae). Using this experimental model we explore the fundamental mechanisms that maintain the eukaryotic proteome folded and functional. Hsp70 belongs to a group of specialized proteins called molecular chaperones that interact with non-natively folded proteins and promote their folding into native conformations. These interactions form the basis for quality control of cellular proteins; a process in which non-natively proteins are recognized and either are routed to folding promoting pathways or removed from the cell via degradation pathways. 

 

A yeast cell in the process of budding off a daugther cell with fluorescently labelled protein aggregates (marker protein Hsp104-EGFP). The cell carries a mutation that inactivates the gene encoding Hsp70 nucleotide exchange factor Fes1 (fes1delta).

 

Keywords

Hsp70, Protein folding, Protein quality control, Protein degradation, ubiquitin, proteasome

Selected publications

Gowda, N.K., Kandasamy, G., Froehlich, M.S., Dohmen, R.J., & Andréasson, C. (2013). Hsp70 nucleotide exchange factor Fes1 is essential for ubiquitin-dependent degradation of misfolded cytosolic proteins. Proc Natl Acad Sci USA. 110(15):5975-80

Andréasson, C., Rampelt, H., Fiaux, J., Druffel-Augustin, S., & Bukau B. (2010). The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp110. J Biol Chem. 285(16):12445-53

Andréasson, C., Fiaux, J., Rampelt, H., Druffel, S. & Bukau, B. (2008). Insights into the structural dynamics of the Hsp110-Hsp70 interaction reveal the mechanism for nucleotide exchange activity. Proc Natl Acad Sci USA. 105(43):16519-24

Sadlish, H., Rampelt, H., Shorter, J., Wegrzyn, R.D., Andréasson, C., Lindquist, S. & Bukau, B. (2008). Hsp110 chaperones regulate prion formation and propagation in S. cerevisiae by two discrete activities. PLoS One. 3(3):e1763

Andréasson, C., Fiaux, J., Rampelt, H., Mayer, M.P. & Bukau, B. (2008). Hsp110 is a nucleotide-activated exchange factor for Hsp70. J Biol Chem. 283(4):8877-84