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Studies of human HSP70 isoforms residing in the cytoplasm and mitochondria and their high molecular weight oligomers: interaction with co-chaperones and client proteins


Among all molecular chaperones, Hsp70 family stands out due to its important role in cellular homeostasis, since they act as a pivot receiving and delivering client proteins from/to other chaperone molecules. Hsp70 act assisting the folding of nascent proteins, preventing protein aggregation, directing of proteins to organelles or for degradation and recovering proteins from aggregates, among others. Therefore, Hsp70s develop crucial functions in cellular proteostasis. This project aims at in-depth studies of the functional mechanism of human Hsp70 residing in cell cytoplasm (Hsp70-1A) and mitochondria (mtHsp70/GRP75/HspA9 /PBP74/mortalin). In mammals, mtHsp70 is also called mortalin due to its involvement with apoptosis, senescence and cancer, as there is a significant change in its level of expression in tumor cells, generating great interest in its study, including as a target for pharmacological inhibition. Although not known since the 1990s, the production of recombinant human mortalin was not possible due to a self-aggregation process, which was recently surpassed by the proponent group. However, Hsp70s undergo self oligomerization/aggregation process, leading to the hypothesis that these would be cellular deposits of Hsp70. Thus, not only the investigation of the structural-functional structure of the monomeric Hsp70, including their regulating factors and interaction with client proteins, is of great relevance as well as the study of Hsp70 oligomers formed in vivo. In this context, this project aims: i) to analyze, in vivo, a presence and functionality of the high molecular weight oligomers of mortalin and Hsp70-1A; ii) to evaluate the in vitro effect of hHep1, hGrpE#1 and hGrpE#2 co-chaperones on mortalin and its high molecular weight oligomers; iii) to obtain the structure and function relationship of human hDjA3 and hDja20 co-chaperones, mitochondrial J-proteins, and evaluate their effects on monomeric mortalin and high molecular weight oligomers and Hsp70-1A; iv) to evaluate the structure of high molecular weight oligomers of mortalin and Hsp70-1A by electron transmission microscopy; v) study the interaction of mortalin, Hsp70-1A and their respective oligomers of high molecular mass with a p53 and mutant client protein, which is involved with a formation of cancerous cells. Both Hsp70-1A and a mortalin (which is also found in the cytoplasm, nucleus and endoplasmic reticulum) act by sequestering the p53 in the cellular cytoplasm, justifying the inclusion of this objective in the proposal. (AU)

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Scientific publications (16)
(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)
SILVA, NOELI S. M.; SERAPHIM, THIAGO V.; MINARI, KARINE; BARBOSA, LEANDRO R. S.; BORGES, JULIO C.. Comparative studies of the low-resolution structure of two p23 co-chaperones for Hsp90 identified in Plasmodium falciparum genome. International Journal of Biological Macromolecules, v. 108, p. 193-204, . (11/23110-0, 12/50161-8, 15/15822-1, 14/07206-6, 17/07335-9, 13/25646-0, 12/01953-9)
SILVA, NOELI S. M.; BERTOLINO-REIS, DAYANE E.; DORES-SILVA, PAULO R.; ANNETA, FATIMA B.; SERAPHIM, THIAGO V.; BARBOSA, LEANDRO R. S.; BORGES, JULIO C.. Structural studies of the Hsp70/Hsp90 organizing protein of Plasmodium falciparum and its modulation of Hsp70 and Hsp90 ATPase activities. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1868, n. 1, . (17/26131-5, 14/07206-6, 11/23110-0, 12/50161-8, 17/07335-9)
TIROLI-CEPEDA, ANA O.; SERAPHIM, THIAGO V.; PINHEIRO, GLAUCIA M. S.; SOUTO, DENIO E. P.; KUBOTA, LAURO T.; BORGES, JULIO C.; BARBOSA, LEANDRO R. S.; RAMOS, CARLOS H. I.. Studies on the effect of the J-domain on the substrate binding domain (SBD) of Hsp70 using a chimeric human J-SBD polypeptide. International Journal of Biological Macromolecules, v. 124, p. 111-120, . (14/07206-6, 17/07335-9, 15/15822-1, 12/50161-8)
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, . (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, . (16/22477-1, 17/07335-9, 14/16646-0, 12/50161-8)
BATISTA, FERNANDA A. H.; RAMOS, JR., SERGIO L.; TASSONE, GIUSY; LEITAO, ANDREI; MONTANARI, CARLOS A.; BOTTA, MAURIZIO; MORI, MATTIA; BORGES, JULIO C.. Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone. Journal of Enzyme Inhibition and Medicinal Chemistry, v. 35, n. 1, p. 639-649, . (13/10712-8, 17/26131-5, 14/07206-6, 11/23110-0, 13/18009-4, 12/50161-8, 17/07335-9)
ALVES BARBOSA, EVERTON DE ALMEIDA; SERAPHIM, THIAGO VARGAS; GANDIN, CESAR AUGUSTO; TEIXEIRA, LEILANE FERREIRA; GONCALVES DA SILVA, RONNI ANDERSON; RIGHETTO, GERMANNA L.; GONCALVES, KALIANDRA DE ALMEIDA; VASCONCELLOS, RAPHAEL DE SOUZA; ALMEIDA, MARCIA ROGERIA; SILVA JUNIOR, ABELARDO; et al. Insights into the full-length SRPK2 structure and its hydrodynamic behavior. International Journal of Biological Macromolecules, v. 137, p. 205-214, . (14/07206-6, 13/50724-5, 11/23110-0, 12/00195-3, 17/03489-1, 12/50161-8, 17/07335-9)
WALBERT VELOSO-SILVA, LAUDIMIR LEONARDO; DORES-SILVA, PAULO ROBERTO; BERTOLINO-REIS, DAYANE ELIARA; MORENO-OLIVEIRA, LOUIS FELLIPE; LIBARDI, SILVIA HELENA; BORGES, JULIO CESAR. Structural studies of Old Yellow Enzyme of Leishmania braziliensis in solution. Archives of Biochemistry and Biophysics, v. 661, p. 87-96, . (14/07206-6, 11/23110-0, 17/07335-9)
SILVA, NOELI S. M.; TORRICILLAS, MARCELA S.; MINARI, KARINE; BARBOSA, LEANDRO R. S.; SERAPHIM, V, THIAGO; BORGES, JULIO C.. Solution structure of Plasmodium falciparum Hsp90 indicates a high flexible dimer. Archives of Biochemistry and Biophysics, v. 690, . (14/07206-6, 17/26131-5, 11/23110-0, 17/07335-9, 12/50161-8)
ROCHA, MARINA CAMPOS; MINARI, KARINE; FABRI, JOAO HENRIQUE TADINI MARILHANO; KERKAERT, JOSHUA D.; GAVA, LISANDRA MARQUES; DA CUNHA, ANDERSON FERREIRA; CRAMER, ROBERT A.; BORGES, JULIO CESAR; MALAVAZI, IRAN. Aspergillus fumigatusHsp90 interacts with the main components of the cell wall integrity pathway and cooperates in heat shock and cell wall stress adaptation. Cellular Microbiology, v. 23, n. 2, . (16/07870-9, 17/26131-5, 17/19694-3, 14/07206-6, 17/07335-9, 15/17541-0)
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, . (17/26131-5, 14/16646-0, 12/50161-8, 17/07335-9, 16/22477-1)
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, . (17/26131-5, 14/07206-6, 11/23110-0, 12/50161-8, 17/07335-9, 14/16646-0)
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, . (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.; 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, . (17/26131-5, 14/16646-0, 12/50161-8, 17/07335-9, 16/22477-1)
COTO, AMANDA L. S.; SERAPHIM, THIAGO V.; BATISTA, FERNANDA A. H.; DORES-SILVA, PAULO R.; BARRANCO, ANA BEATRIZ F.; TEIXEIRA, FELIPE R.; GAVA, LISANDRA M.; BORGES, JULIO C.. Structural and functional studies of the Leishmania braziliensis SGT co-chaperone indicate that it shares structural features with HIP and can interact with both Hsp90 and Hsp70 with similar affinities. International Journal of Biological Macromolecules, v. 118, n. A, p. 693-706, . (14/07206-6, 17/07335-9, 12/50161-8)
MINARI, KARINE; DE AZEVEDO, ERIKA CHANG; RODRIGUES KIRALY, VANESSA THOMAZ; HELENO BATISTA, FERNANDA APARECIDA; DE MORAES, FABIO ROGERIO; DE MELO, FERNANDO ALVES; NASCIMENTO, ALESSANDRO SILVA; GAVA, LISANDRA MARQUES; INACIO RAMOS, CARLOS HENRIQUE; BORGES, JULIO CESAR. Thermodynamic analysis of interactions of the Hsp90 with adenosine nucleotides: A comparative perspective. International Journal of Biological Macromolecules, v. 130, p. 125-138, . (09/53989-4, 11/23110-0, 15/26722-8, 12/50161-8, 14/07206-6, 17/18173-0, 17/07335-9, 13/25646-0)

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