Abstract
The Human mitochondrial Hsp70 (mtHsp70, also known as mortalin) is involved in a range of cellular processes, where it has paradox roles: while it helps keeping cellular homeostasis, its malfunction is involved in degenerative disorders. In the mitochondrion matrix, mortalin acts in the process of protein importation from cytoplasm; in the cytoplasm, it may works as a p53 scavenger, therefore associated to cancer progression and proliferation. Besides, recent data suggests mortalin as involved in Parkinson's, Alzheimer's and other age-associated diseases. Thereby, in vitro and in vivo structural and functional investigation of Mortalin, as well as its functional interaction with other chaperones, as well as physical interaction with co-chaperones and client proteins, is of great relevance for a better understanding of its cellular roles and the biochemical machinery of the involved diseases. This knowledge is critical for the development of new drugs acting in this system, which makes of mortalin a potential therapeutic target. Despite being known for a long time, the expression of heterologous mortalin resulted in an insoluble form of the protein, which precludes its in vitro structural and functional studies. Thus, structural and functional information of this protein, along with its interaction with chaperones, co-chaperones and client proteins, remained unknown. The BBP lab (laboratory of Protein Biochemistry and Biophysics) has developed a new protocol for mortalin production resulting in the obtainment of its native recombinant form, which allows studies and experimentations. Thus the data will contribute for a better understanding of structural and functional differences between mortalin and other Hsp70. However, many other questions are still unanswered. This project aims to continue the studies with mortalin, investigating its interaction and the structure of complexes formed with its co-chaperones GrpEs, Hsp40 and hHep1; with other non-chaperone molecules, such as wild-type and mutated p53, and the di- and triphosphate adenosine nucleotides; and with MKT-077, an specific mortalin inhibitor. Also, this project aims studying the roles of this molecule in the formation of vesicles, this part to be carried out in the University of California at San Diego through the Latin America-UC San Diego Science Connect program, under co-supervision of Professor Dr. Antonio de Maio. (AU)
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