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Human mortalin: interaction with co-chaperones, p53 and mutants, aggregation kinectics, regulation/modulation and vesicle secretion

Grant number: 14/16646-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2015
Effective date (End): October 31, 2018
Field of knowledge:Biological Sciences - Biochemistry
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Julio Cesar Borges
Grantee:Paulo Roberto das Dores da Silva
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:12/50161-8 - Study of the structure and function of the Hsp90 chaperone with emphasis on its role in cellular homeostasis, AP.TEM
Associated scholarship(s):16/22477-1 - Human mortalin: interaction with liposomes, mitochondrion membrane, beta-amyloids and effect of its presence in the toxicity of beta-amyloids on neurons, BE.EP.PD

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)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BATISTA, FERNANDA A. H.; DORES-SILVA, PAULO R.; BORGES, JULIO C. Molecular Chaperones Involved in Protein Recovery from Aggregates are Present in Protozoa Causative of Malaria and Leishmaniasis. CURRENT PROTEOMICS, v. 16, n. 1, p. 12-21, 2019. Web of Science Citations: 0.
DORES-SILVA, PAULO R.; NISHIMURA, LETICIA S.; KIRALY, VANESSA T. R.; BORGES, JULIO C. Structural and functional studies of the Leishmania braziliensis mitochondrial Hsp70: Similarities and dissimilarities to human orthologues. Archives of Biochemistry and Biophysics, v. 613, p. 43-52, JAN 1 2017. Web of Science Citations: 2.
DORES-SILVA, P. R.; BELOTI, L. L.; MINARI, K.; SILVA, S. M. O.; BARBOSA, L. R. S.; BORGES, J. C. Structural and functional studies of Hsp70-escort protein-Hep1-of Leishmania braziliensis. International Journal of Biological Macromolecules, v. 79, p. 903-912, AUG 2015. Web of Science Citations: 4.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.