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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

Grant number: 17/07335-9
Support type:Regular Research Grants
Duration: August 01, 2017 - July 31, 2019
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Julio Cesar Borges
Grantee:Julio Cesar Borges
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated scholarship(s):18/07713-6 - Technical support to project "Studies of human HSP70 isoforms residing in the cytoplasm and mitochondria and their high molecular weight oligomers: interaction with co-chaperones and client proteins", BP.TT

Abstract

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)

Scientific publications (7)
(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.; 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 JAN 2020. Web of Science Citations: 0.
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; RANGEL FIETTO, JULIANA LOPES; KOBARG, JORG; GILEADI, CARINA; MASSIRER, KATLIN B.; BORGES, JULIO CESAR; NETO, MARIO DE OLIVEIRA; BRESSAN, GUSTAVO COSTA. Insights into the full-length SRPK2 structure and its hydrodynamic behavior. International Journal of Biological Macromolecules, v. 137, p. 205-214, SEP 15 2019. Web of Science Citations: 0.
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, JUN 1 2019. Web of Science Citations: 1.
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, MAR 1 2019. Web of Science Citations: 0.
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, JAN 2019. Web of Science Citations: 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, OCT 15 2018. Web of Science Citations: 1.
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, MAR 2018. Web of Science Citations: 3.

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