The process in which a newly synthesized polypeptide chain transforms itself into a perfectly folded protein depends both on the properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu. Uncovering the mechanism of protein folding and unfolding is one of the grand challenges of modern science. The three-dimensional arrangement of the polypeptide chain decide about the specific biological function of the protein in the cell. Only correctly folded proteins are fully functional, randomly arranged polypeptide chain doesn't have biological activity. The state of protein folding is controlled and regulated by the protein quality control system. The system is formed by chaperones involved in protein folding and the proteasomal degradation system. The proper functioning of the system is required because its dysfunction may lead to neurodegenerative diseases. The prion-related illnesses such as Creutzfeldt-Jakob disease, amyloid-related illnesses such as Alzheimer's disease as well as intracytoplasmic aggregation diseases such as Huntington's and Parkinson's disease those are neurodegenerative diseases whose pathogenesis is associated with protein aggregation of incorrectly folded proteins.
Many chaperones are heat shock proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress conditions. The project focuses on the protein Hsp104 which belongs to the Hsp100 family and the AAA+ superfamily. Hsp104 is important in the cell due to its ability to solubilize and refold proteins trapped in aggregates formed during heat stress [1]. It achieves this in cooperation with the Hsp70 chaperone system. The active form of the protein is a ring-shaped hexamer, which is thought to drive protein disaggregation by directly translocating substrates through its central channel. However, there is still no general consensus regarding the domain organization within the hexameric molecular machine. Substantial efforts have been made to elucidate the location of domain M, but the results are contradictory [2, 3]. We aim to learn the location and the orientation of the unique M domain by solving the crystal structure of Hsp104 using X-ray crystallography.
This work was supported by Grant 2013/08/S/NZ1/00750 from National Science Center (NCN)