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 - Chemistry of Macromolecules
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal researcher: 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 their 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

(9)

(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)

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. (14/16646-0, 14/07206-6, 11/23110-0)

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. (14/07206-6, 14/16646-0, 12/50161-8, 11/23110-0)

DORES-SILVA, PAULO ROBERTO; RODRIGUES KIRALY, VANESSA THOMAZ; DE OLIVEIRA MORITZ, MILENE NOBREGA; BALASCO SERRAO, VITOR HUGO; SIQUEIRA DOS PASSOS, PATRICIA MARIA; SPAGNOL, VALENTINE; TEIXEIRA, FELIPE ROBERTI; GAVA, LISANDRA MARQUES; CAUVI, DAVID MARIO; INACIO RAMOS, CARLOS HENRIQUE; et al. New insights on human Hsp70-escort protein 1: Chaperone activity, interaction with liposomes, cellular localizations and HSPA's self-assemblies remodeling. International Journal of Biological Macromolecules, v. 182, p. 772-784, JUL 1 2021. (14/16646-0, 14/07206-6, 17/26131-5, 16/25798-3, 09/54216-9, 12/50161-8, 17/07879-9, 11/23110-0, 17/07335-9, 12/23730-1)

DORES-SILVA, PAULO ROBERTO; CAUVI, DAVID M.; KIRALY, VANESSA T. R.; BORGES, JULIO C.; DE MAIO, ANTONIO. Human HSPA9 (mtHsp70, mortalin) interacts with lipid bilayers containing cardiolipin, a major component of the inner mitochondrial membrane. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, v. 1862, n. 11, NOV 1 2020. (16/22477-1, 17/07335-9, 14/16646-0, 12/50161-8)

MELO SILVA, NOELI SOARES; DE CAMARGO RODRIGUES, LUIZ FERNANDO; DORES-SILVA, PAULO ROBERTO; MONTANARI, CARLOS ALBERTO; INACIO RAMOS, CARLOS HENRIQUE; SOUZA BARBOSA, LEANDRO RAMOS; BORGES, JULIO CESAR. Structural, thermodynamic and functional studies of human 71 kDa heat shock cognate protein (HSPA8/hHsc70). BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1869, n. 12, DEC 2021. (17/07335-9, 11/23110-0, 17/26131-5, 12/50161-8, 15/15822-1, 14/07206-6, 14/16646-0)

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. (11/23110-0, 14/07206-6, 14/16646-0, 12/50161-8)

KIRALY, VANESSA T. R.; DORES-SILVA, PAULO R.; SERRAO, VITOR H. B.; CAUVI, DAVID M.; DE MAIO, ANTONIO; BORGES, JULIO C.. Thermal aggregates of human mortalin and Hsp70-1A behave as supramolecular assemblies. International Journal of Biological Macromolecules, v. 146, p. 320-331, MAR 1 2020. (17/26131-5, 14/07206-6, 11/23110-0, 12/50161-8, 17/07335-9, 14/16646-0)

DORES-SILVA, PAULO ROBERTO; CAUVI, DAVID M.; COTO, AMANDA L. S.; KIRALY, VANESSA T. R.; BORGES, JULIO C.; DE MAIO, ANTONIO. Interaction of HSPA5 (Grp78, BIP) with negatively charged phospholipid membranes via oligomerization involving the N-terminal end domain. CELL STRESS & CHAPERONES, v. 25, n. 6, JUL 2020. (17/26131-5, 12/50161-8, 16/22477-1, 17/07335-9, 14/16646-0)

DORES-SILVA, PAULO R.; CAUVI, DAVID M.; COTO, AMANDA L. S.; SILVA, NOELI S. M.; BORGES, JULIO C.; DE MAIO, ANTONIO. Human heat shock cognate protein (HSC70/HSPA8) interacts with negatively charged phospholipids by a different mechanism than other HSP70s and brings HSP90 into membranes. CELL STRESS & CHAPERONES, v. 26, n. 4, p. 671-684, JUL 2021. (17/26131-5, 14/16646-0, 12/50161-8, 17/07335-9, 16/22477-1)