The chaperome: study of the relationship of the structure of its components and the maintenance of proteostasis

• Grant number: 17/26131-5
• Support Opportunities: Research Projects - Thematic Grants
• Duration: March 01, 2019 - August 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Carlos Henrique Inacio Ramos
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Julio Cesar Borges ; Leandro Ramos Souza Barbosa
• Associated researchers: Denize Cristina Favaro ; Leandro Ramos Souza Barbosa ; Lisandra Marques Gava Borges
• Associated grant(s): 24/02293-0 - The Role of Phosphorylation in Modulating Hsp90 Chaperone Activity and its Co-chaperones SGT and Aha1, AP.R; 23/01237-6 - Mapping contact regions between cochaperones from Hsp40 family and proteins involved in amyloidogenic diseases towards the understanding of the mechanisms for protein aggregates reactivation, AP.R; 22/03729-0 - Characterization of posttranslational modifications that modulate DNAJB1, a targeting factor of the human Hsp70-based protein disaggregase, AP.R
• Associated scholarship(s): 24/04401-4 - Biochemical evaluation of the redox state in the formation and stability of HSPA5 supramolecular complexes (BiP), BP.IC; 24/01429-5 - Investigation of the structure-function relationship of Aedes aegypti proteins RPAP3, Pih1D1, WDR92 and their role in insect development, BP.DR; 24/04991-6 - Technical assistance: Chaperome., BP.TT; + associated scholarships 23/13154-8 - Technical assistance in the development of research linked to a thematic project., BP.TT; 23/08849-7 - Assembly and application of a chaperone activity test platform, BP.TT; 23/06528-9 - Auxílio técnico em projeto temático, BP.TT; 23/06769-6 - Technical assistance: Chaperome., BP.TT; 22/15523-8 - Technical assistance: Chaperome., BP.TT; 22/09729-2 - Technical assistance in the development of research linked to a thematic project., BP.TT; 22/08855-4 - Study of interactions between chaperome components, BP.PD; 22/08968-3 - Technical assitance in Thematic Project., BP.TT; 22/07497-7 - Technical assistance: Chaperome., BP.TT; 22/02672-5 - THE CHAPEROME: STUDY OF THE RELATIONSHIP OF THE STRUCTURE OF ITS COMPONENTS AND THE MAINTENANCE OF PROTEOSTASIS, BP.TT; 21/02289-4 - Structural studies of the Activator of HSP90 ATPase (Aha) co-chaperone isoforms in Plasmodium falciparum in complex with the HSP90 chaperone and characterization of their cellular roles, BP.PD; 20/15947-7 - Mapping and mechanistic characterization of the interaction of the human HspA5 (BiP/Grp78/erHsp70) protein with the human Hep1 co-chaperone and with the Spike protein of the SARS-CoV-2 Coronavirus, BP.PD; 21/04799-0 - Functional and structural characterization of truncated mutants of human Hsp70-escort protein 1, BP.IC; 21/02629-0 - The chaperome: study of the relationship of the structure of its components and the maintenance of proteostasis, BP.TT; 20/11645-6 - Conformational and functional characterization of Aedes aegypti Hsp70 chaperone, BP.IC; 19/22422-0 - Cellular functional study of high molecular weight oligomers of mortaline and the effects of mitochondrial co-chaperones on their structure, BP.PD; 19/14209-5 - Analysis and characterization of the n- and C- terminal domains of human BiP protein (HspA5), BP.IC; 19/16114-1 - Structure / function relationship of the Hsp40s., BP.PD; 19/09370-1 - THE CHAPEROME: STUDY OF THE RELATIONSHIP OF THE STRUCTURE OF ITS COMPONENTS AND THE MAINTENANCE OF PROTEOSTASIS, BP.TT; 19/09371-8 - The chaperome: study of the relationship of the structure of its components and the maintenance of proteostasis, BP.TT; 19/09778-0 - THE CHAPEROME: STUDY OF THE RELATIONSHIP OF THE STRUCTURE OF ITS COMPONENTS AND THE MAINTENANCE OF PROTEOSTASIS, BP.TT - associated scholarships

Abstract

One of the most interesting challenges in science is the understanding of the structure/function relationship of proteins because these macromolecules are involved in virtually all cellular physiological functions. Accordingly, this knowledge can have several applications, including the production of proteins with specific functions and defined biotechnological applications. As the loss of the structure also leads to loss of function and to a high degree of cellular damage, there is also medicinal interest in this knowledge since it can generate strategies for therapeutic interventions with broad applications such as aging, stress, neurodegenerative diseases and tumor. The research groups gathered around this proposal have a high interest in the understanding of protein folding and the structure/function relationship of proteins. This research proposal focuses on the study of the chaperome, a cellular network aimed at the maintenance of homeostasis, which includes aiding the folding of several proteins, preventing unfolding in stress situations and promoting the recovery and degradation of protein aggregates. Additionally, the components of the chaperome are involved in several other complementary functions, among which the most important are maintenance of proteostasis in stress situations, signaling, phenotype stabilization, mitochondria biogenesis, immunity, preventing amyloidogenesis, etc. Our proposal aims at the production and characterization of the components of the chaperome and the investigation of the interaction between them and with client proteins. The proposal is divided between challenging but high-attainable goals and high-risk/high-gain objectives that will enable us to advance the frontier of knowledge in the area. Previous results have shown that different organisms have certain particularities in the structure/function relationship of the chaperome (for instance, the number and diversity of co-chaperones increases with organism complexity), showing that it is crucial to study the system of several species to obtain information on the functioning of this system. The same reasoning can be extrapolated to organelles since each one has its own set of chaperones/Hsps. Therefore, we chose highly relevant targets for global science and potential applications in Brazil: human being, sugarcane, Aedes aegypti, Leishmania sp, Plasmodium falciparum and yeast; cytoplasmic and mitochondrial. Therefore, this proposal has great potential to generate relevant knowledge both in the medical field, by generating strategies aimed at therapeutic intervention, and in biotechnology, by generating innovative processes in plants and microorganisms aiming to produce potential biotechnological tools. (AU)

Scientific publications

(25)

(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)

ARAUJO, SARA A.; MARTINS, GUSTAVO H.; QUEL, NATALIA G.; ARAGAO, ANNELIZE Z. B.; MOREA, EDNA G. O.; BORGES, JULIO C.; HOURY, WALID A.; CANO, MARIA I. N.; RAMOS, I, CARLOS H.. Purification and characterization of a novel and conserved TPR-domain protein that binds both Hsp90 and Hsp70 and is expressed in all developmental stages of Leishmania major. Biochimie, v. 182, p. 51-60, MAR 2021. (14/25967-4, 12/50161-8, 19/11496-3, 18/04375-2, 17/26131-5)

FRANCO, JULIANA C.; NOGUEIRA, MARIA L. C.; GANDELINI, GABRIELA M.; PINHEIRO, GLAUCIA M. S.; GONCALVES, CONRADO C.; BARBOSA, LEANDRO R. S.; YOUNG, JASON C.; RAMOS, CARLOS H. I.. Sorghum bicolor SbHSP110 has an elongated shape and is able of protecting against aggregation and replacing human HSPH1/HSP110 in refolding and disaggregation assays. Biopolymers, v. 114, n. 2, p. 12-pg., 2023-02-01. (16/02137-1, 12/50161-8, 16/14503-2, 16/04246-2, 16/03764-0, 18/11948-9, 17/26131-5)

MAIMONI CAMPANELLA, JONATAS ERICK; RAMOS JUNIOR, SERGIO LUIZ; RODRIGUES KIRALY, VANESSA THOMAZ; SEVERO GOMES, ANTONIEL AUGUSTO; DE BARROS, ANDREA COELHO; MATEOS, PABLO ACERA; FREITAS, FERNANDA ZANOLLI; DE MATTOS FONTES, MARCOS ROBERTO; BORGES, JULIO CESAR; BERTOLINI, MARIA CELIA. Biochemical and biophysical characterization of the RVB-1/RVB-2 protein complex, the RuvBL/RVB homologues in Neurospora crassa. Biochimie, v. 191, p. 11-26, DEC 2021. (17/26131-5, 08/57566-8)

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, 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)

SERAPHIM, V, THIAGO; NANO, NARDIN; CHEUNG, YIU WING SUNNY; ALUKSANASUWAN, SIRIPAT; COLLETI, CAROLINA; MAO, YU-QIAN; BHANDARI, VAIBHAV; YOUNG, GAVIN; HOLL, LARISSA; PHANSE, SADHNA; et al. ssembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexe. Structure, v. 30, n. 1, p. 156+, JAN 6 2022. (17/26131-5, 12/50161-8, 15/15822-1, 16/05019-0, 16/01603-9, 12/01953-9)

GONCALVES, CONRADO C.; SHARON, ITAI; SCHMEING, T. MARTIN; RAMOS, I, CARLOS H.; YOUNG, JASON C.. The chaperone HSPB1 prepares protein aggregates for resolubilization by HSP70. SCIENTIFIC REPORTS, v. 11, n. 1, AUG 24 2021. (17/26131-5, 16/03764-0)

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. (17/26131-5, 14/07206-6, 11/23110-0, 12/50161-8, 17/07335-9)

ANTONIO, LARISSA MACHADO; MARTINS, GUSTAVO HENRIQUE; ARAGAO, ANNELIZE ZAMBON BARBOSA; QUEL, NATALIA GALDI; ZAZERI, GABRIEL; HOURY, WALID A.; RAMOS, CARLOS HENRIQUE INACIO. Unveiling the Role of Sorghum RPAP3 in the Function of R2TP Complex: Insights into Protein Assembly in Plants. PLANTS-BASEL, v. 12, n. 16, p. 15-pg., 2023-08-01. (22/01955-3, 12/50161-8, 22/08855-4, 17/26131-5)

DE JESUS, JEMMYSON ROMARIO; BARBOSA ARAGAO, ANNELIZE ZAMBON; ZEZZI ARRUDA, MARCO AURELIO; RAMOS, CARLOS H., I. Optimization of a Methodology for Quantification and Removal of Zinc Gives Insights Into the Effect of This Metal on the Stability and Function of the Zinc-Binding Co-chaperone Ydj1. RONTIERS IN CHEMISTR, v. 7, p. 10-pg., 2019-06-11. (17/26131-5, 12/50161-8, 18/00768-0)

DE JESUS, JEMMYSON ROMARIO; BARBOSA ARAGAO, ANNELIZE ZAMBON; ZEZZI ARRUDA, MARCO AURELIO; RAMOS, I, CARLOS H.. Optimization of a Methodology for Quantification and Removal of Zinc Gives Insights Into the Effect of This Metal on the Stability and Function of the Zinc-Binding Co-chaperone Ydj1. FRONTIERS IN CHEMISTRY, v. 7, JUN 11 2019. (17/26131-5, 12/50161-8, 18/00768-0)

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, SEP 15 2020. (14/07206-6, 17/26131-5, 11/23110-0, 17/07335-9, 12/50161-8)

QUEL, NATALIA G.; PINHEIRO, GLAUCIA M. S.; RODRIGUES, LUIZ FERNANDO DE C.; BARBOSA, LEANDRO R. S.; HOURY, WALID A.; RAMOS, I, CARLOS H.. Heat shock protein 90 kDa (Hsp90) from Aedes aegypti has an open conformation and is expressed under heat stress. International Journal of Biological Macromolecules, v. 156, p. 522-530, AUG 1 2020. (17/26131-5, 16/05019-0, 15/15822-1, 14/25967-4, 12/01953-9)

SOUTO, DENIO E. P.; VOLPE, JAQUELINE; GONCALVES, CONRADO DE C.; RAMOS, I, CARLOS H.; KUBOTA, LAURO T.. A brief review on the strategy of developing SPR-based biosensors for application to the diagnosis of neglected tropical diseases. Talanta, v. 205, DEC 1 2019. (17/26131-5, 17/26058-6, 14/50867-3, 13/22127-2)

PINHEIRO, GLAUCIA M. S.; AMORIM, GISELE C.; IQBAL, ANWAR; ALMEIDA, FABIO C. L.; RAMOSA, C. H. I.. Solution NMR investigation on the structure and function of the isolated J-domain from Sis1: Evidence of transient inter-domain interactions in the full-length protein. Archives of Biochemistry and Biophysics, v. 669, p. 71-79, JUL 15 2019. (17/26131-5, 12/50161-8, 17/01074-9, 18/11948-9)

RAMOS, I, CARLOS H.; AYINDE, KEHINDE S.. Are Hsp90 Inhibitors Good Candidates Against Covid-19?. CURRENT PROTEIN & PEPTIDE SCIENCE, v. 22, n. 3, p. 192-200, 2021. (17/26131-5)

FREITAS, FREDERICO CAMPOS; BORGES FERREIRA, PAULO HENRIQUE; FAVARO, DENIZE CRISTINA; DE OLIVEIRA, RONALDO JUNIO. Shedding Light on the Inhibitory Mechanisms of SARS-CoV-1/CoV-2 Spike Proteins by ACE2-Designed Peptides. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 61, n. 3, p. 1226-1243, MAR 22 2021. (17/26131-5, 17/22822-3)

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 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. (14/16646-0, 17/26131-5, 12/50161-8, 16/22477-1, 17/07335-9)

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)

QUEL, NATALIA G.; RODRIGUES, LUIZ FERNANDO DE C.; ARAGAO, ANNELIZE Z. B.; PINHEIRO, GLAUCIA M. S.; CAMACHO, RAFAEL P.; SOUTO, DENIO E. P.; KUBOTA, LAURO T.; BARBOSA, LEANDRO R. S.; RAMOS, CARLOS H. I.. Insights into the structure and function of the C-terminus of SGTs (small glutamine-rich TPR-containing proteins): A study of the Aedes aegypti homolog. Biochimie, v. 187, p. 131-143, AUG 2021. (16/05019-0, 12/01953-9, 14/25967-4, 17/26131-5, 15/15822-1)

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, MAR 1 2020. (17/26131-5, 14/07206-6, 11/23110-0, 12/50161-8, 17/07335-9, 14/16646-0)

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, JAN 1 2020. (13/10712-8, 17/26131-5, 14/07206-6, 11/23110-0, 13/18009-4, 12/50161-8, 17/07335-9)

DE JESUS, JEMMYSON R.; LINHARES, LEONARDO A.; ARAGA, ANNELIZE Z. B.; ARRUDA, MARCO A. Z.; RAMOS, CARLOS H. I.. The stability and function of human cochaperone Hsp40/DNAJA1 are affected by zinc removal and partially restored by copper. Biochimie, v. 213, p. 7-pg., 2023-05-30. (17/26131-5, 19/24445-8, 14/50867-3, 18/00768-0, 18/25207-0, 20/08543-7)

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, FEB 2021. (16/07870-9, 14/07206-6, 17/19694-3, 15/17541-0, 17/26131-5, 17/07335-9)

AYINDE, KEHINDE S.; PINHEIRO, GLAUCIA M. S.; RAMOS, CARLOS H. I.. Binding of SARS-CoV-2 protein ORF9b to mitochondrial translocase TOM70 prevents its interaction with chaperone HSP90. Biochimie, v. 200, p. 8-pg., 2022-09-01. (17/26131-5, 18/11948-9)