Study of the structure and function of the Hsp90 chaperone with emphasis on its role in cellular homeostasis

• Grant number: 12/50161-8
• Support type: Research Projects - Thematic Grants
• Duration: August 01, 2012 - July 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Carlos Henrique Inacio Ramos
• Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Co-Principal Investigators: Julio Cesar Borges ; Maria Isabel Nogueira Cano
• Associated grant(s): 16/16277-0 - 2nd Annual European MicroCal Meeting, AR.EXT
• Associated scholarship(s): 17/01074-9 - HSP90 interaction with other proteins and cofactors, BP.PD; 16/20405-3 - Production of recombinant mitochondrial Hsp70 chaperone of Plasmodium falciparum aiming structural characterization and functional, BP.IC; 16/14228-1 - Hsp90 interaction with other proteins, BP.PD; + associated scholarships 16/14503-2 - Thermodynamic characterization of Hsp90 interaction with other proteins, BP.PD; 15/08909-3 - Investigation of molecular chaperones cell expression and their function by complementation in knockout yeasts, BP.PD; 14/16646-0 - Human mortalin: interaction with co-chaperones, p53 and mutants, aggregation kinectics, regulation/modulation and vesicle secretion, BP.PD; 14/15432-6 - Effect of catechin EGCG in assembly of Hsp90 complex: co-chaperones, BP.IC; 14/08786-6 - Structural and functional study of the co-chaperone SGT of Leishmania braziliensis, BP.MS; 14/00076-0 - Study of important chaperone-interaction from the celular protein quality control system in higher eukaryotes., BP.DR; 14/00170-6 - Study of Hsp90 interaction with other proteins by cross-linking and investigation of metals binding and their effects, BP.PD; 13/25646-0 - Comparative functional studies of Hsp90 from different organisms, BP.DD; 13/16813-0 - Study of cytoplasmic and mitochondrial Hsp70 chaperones from of Plasmodium falciparum and Leishmania braziliensis and their interaction with co-chaperones and potential ligands/inhibitors., BP.PD; 13/11500-4 - Studies of proteins in the Eukaryotic hsp90 proteomic hub: Functional characterization of the human and Leishmania braziliensis p23 co-chaperones and a possible metazoan hsp100/clpB ortholog utilizing yeast as a surrogate expression system, BP.PD; 13/10712-8 - Identifying Molecules with Selective Inhibitory Action for leishmania, plasmodium and human Hsp90 ortologues: Thermodynamic and Comparative approach., BP.PD; 13/10939-2 - Characterization of human genes as potential chaperone with desagregase function, BP.DR; 12/25475-9 - Studying telomere homeostasis in Leishmania spp. by using Hsp90 and telomerase inhibitors, BP.PD - associated scholarships

Abstract

The Hsp90 chaperone (heat shock protein 90 kDa) is found in all organisms and in all cellular compartments, and the two types found in the eukaryotic cytosol interact with at least 10% of all proteins produced by the cell. The Hsp90 plays a key role in the maturation of these proteins, which makes it important for many cellular processes such signaling, proteostasis, epigenetics, telomere maintenance, innate immunity, etc. Obviously, changes in this 'highly connected node', as one can label Hsp90, leads to disturbances in cell function resulting in drastic consequences for the organism. For example, Hsp90 appears to play a central role in the pathology of several types of cancer as many kinases are clients and are involved in the development of cancer. As a matter of fact, specific inhibitors of Hsp90 and co-chaperones are under investigation in clinical trials. No human cytosolic Hsp90 had its full three-dimensional structure determined and the mechanisms by which this chaperone functions and is modulated are not yet fully known. Even the set of co-chaperones and post-translational modifications, that play key role in the processes aforementioned, are not yet complete understood. The obvious therapeutic potential that Hsp90 from human, and Hsp90 from other organisms, have, make essential to unravel the forces that stabilize their structure and the mechanisms by which their functions are modulated resulting in the maturation of proteins clients. The importance in studying Hsp90 brought together researchers involved in studying the relationship between structure and function of proteins, particularly chaperones from human, plants and protozoa, that will focus on the following goals: 1) Determination of the conformational aspects of Hsp90, its isolated domains and some of its co-chaperones. 2) Characterization of the ATPase activity of the various types of Hsp90 available. 3) Investigation of the interaction of Hsp90 with several co-chaperones, inhibitors and client proteins. 4) Investigation of the effect that post-translational modifications have in the structure and function of Hsp90. To show our commitment to this proposal we would like to stress that some studies are already underway and already have potential to generate knowledge that is both new and relevant. (AU)

Scientific publications

(34)

(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, 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. Web of Science Citations: 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. Web of Science Citations: 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. Web of Science Citations: 2.

GONCALVES, CONRADO DE C.; PINHEIRO, GLAUCIA M. S.; DAHLSTROM, KATHE M.; SOUTO, DENIO E. P.; KUBOTA, LAURO T.; BARBOSA, LEANDRO R. S.; RAMOS, I, CARLOS H. On the structure and function of Sorghum bicolor CHIP (carboxyl terminus of Hsc70-interacting protein): A link between chaperone and proteasome systems. Plant Science, v. 296, JUL 2020. Web of Science Citations: 0.

NANO, NARDIN; UGWU, FRANCISCA; SERAPHIM, V, THIAGO; LI, TANGZHI; AZER, GINA; ISAAC, METHVIN; PRAKESCH, MICHAEL; BARBOSA, LEANDRO R. S.; RAMOS, I, CARLOS H.; DATTI, ALESSANDRO; HOURY, WALID A. Sorafenib as an Inhibitor of RUVBL2. BIOMOLECULES, v. 10, n. 4 APR 2020. Web of Science Citations: 0.

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. Web of Science Citations: 0.

STORTI, CAMILA BALDIN; DE OLIVEIRA, ROGERIO ANTONIO; DE CARVALHO, MARCIO; HASIMOTO, ERICA NISHIDA; CATANEO, DANIELE CRISTINA; MARIA CATANEO, ANTONIO JOSE; DE FAVERI, JULIO; VASCONCELOS, ELTON JOSE R.; DOS REIS, PATRICIA PINTOR; NOGUEIRA CANO, MARIA ISABEL. Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC). Experimental and Molecular Pathology, v. 112, FEB 2020. Web of Science Citations: 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. Web of Science Citations: 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. Web of Science Citations: 0.

MABANGLO, MARK F.; LEUNG, ELISA; VAHIDI, SIAVASH; SERAPHIM, V, THIAGO; EGER, BRYAN T.; BRYSON, STEVE; BHANDARI, VAIBHAV; ZHOU, JIN LIN; MAO, YU-QIAN; RIZZOLO, KAMRAN; BARGHASH, MARIM M.; GOODREID, JORDAN D.; PHANSE, SADHNA; BABU, MOHAN; BARBOSA, LEANDRO R. S.; RAMOS, I, CARLOS H.; BATEY, ROBERT A.; KAY, LEWIS E.; PAI, EMIL F.; HOURY, WALID A. ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores. COMMUNICATIONS BIOLOGY, v. 2, NOV 13 2019. 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.

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. Web of Science Citations: 1.

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. 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.

ADAO, REGINA; ZANPHORLIN, LETICIA M.; LIMA, TATIANI B.; SRIRANGANADANE, DEV; DAHLSTROM, KATHE M.; PINHEIRO, GLAUCIA M. S.; GOZZO, FABIO C.; BARBOSA, LEANDRO R. S.; RAMOS, CARLOS H. I. Revealing the interaction mode of the highly flexible Sorghum bicolor Hsp70/Hsp90 organizing protein (Hop): A conserved carboxylate clamp confers high affinity binding to Hsp90. JOURNAL OF PROTEOMICS, v. 191, n. SI, p. 191-201, JAN 16 2019. Web of Science Citations: 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. Web of Science Citations: 0.

VIVIESCAS, MARIA ALEJANDRA; NOGUEIRA CANO, MARIA ISABEL; SEGATTO, MARCELA. Chaperones and Their Role in Telomerase Ribonucleoprotein Biogenesis and Telomere Maintenance. CURRENT PROTEOMICS, v. 16, n. 1, p. 31-43, 2019. Web of Science Citations: 0.

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.

PINHEIRO, GLAUCIA M. S.; RAMOS, CARLOS H. I. Initial characterization of newly identified mitochondrial and chloroplast small HSPs from sugarcane shows that these chaperones have different oligomerization states and substrate specificities. Plant Physiology and Biochemistry, v. 129, p. 285-294, AUG 2018. Web of Science Citations: 1.

MOHAMMADI-OSTAD-KALAYEH, SONA; STAHL, FRANK; SCHEPER, THOMAS; KOCK, KLAUS; HERRMANN, CHRISTIAN; BATISTA, FERNANDA APARECIDA HELENO; BORGES, JULIO CESAR; SASSE, FLORENZ; EICHNER, SIMONE; ONGOUTA, JEKATERINA; ZEILINGER, CARSTEN; KIRSCHNING, ANDREAS. Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s. CHEMBIOCHEM, v. 19, n. 6, p. 562-574, MAR 16 2018. Web of Science Citations: 4.

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.

MOREA, EDNA G. O.; VIVIESCAS, MARIA ALEJANDRA; FERNANDES, CARLOS A. H.; MATIOLI, FABIO F.; LIRA, CRISTINA B. B.; FERNANDEZ, MARIBEL F.; MORAES, BARBARA S.; DA SILVA, MARCELO S.; STORTI, CAMILA B.; FONTES, MARCOS R. M.; CANO, MARIA ISABEL N. A calmodulin-like protein (LCALA) is a new Leishmania amazonensis candidate for telomere end-binding protein. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1861, n. 11, A, p. 2583-2597, NOV 2017. Web of Science Citations: 1.

MOKRY, DAVID Z.; DA SILVA, VIVIANE C. H.; ABRAHAO, JOSIELLE; RAMOS, CARLOS H. I. Characterization of the Hsp100 disaggregase from sugarcane (SHsp101) for chaperone like activity in a yeast system. JOURNAL OF PLANT BIOCHEMISTRY AND BIOTECHNOLOGY, v. 26, n. 4, p. 478-487, OCT 2017. Web of Science Citations: 0.

SERAPHIM, THIAGO V.; SILVA, KELLY P.; DORES-SILVA, PAULO R.; BARBOSA, LEANDRO R. S.; BORGES, JULIO C. Insights on the structural dynamics of Leishmania braziliensis Hsp90 molecular chaperone by small angle X-ray scattering. International Journal of Biological Macromolecules, v. 97, p. 503-512, APR 2017. Web of Science Citations: 6.

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.

ABRAHAO, JOSIELLE; MOKRY, DAVID Z.; RAMOS, CARLOS H. I. Hsp78 (78 kDa Heat Shock Protein), a Representative AAA Family Member Found in the Mitochondrial Matrix of Saccharomyces cerevisiae. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 4, 2017. Web of Science Citations: 2.

ZANPHORLIN, LETICIA M.; LIMA, TATIANI B.; WONG, MICHAEL J.; BALBUENA, TIAGO S.; MINETTI, CONCEICAO A. S. A.; REMETA, DAVID P.; YOUNG, JASON C.; BARBOSA, LEANDRO R. S.; GOZZO, FABIO C.; RAMOS, CARLOS H. I. Heat Shock Protein 90 kDa (Hsp90) Has a Second Functional Interaction Site with the Mitochondrial Import Receptor Tom70. Journal of Biological Chemistry, v. 291, n. 36, p. 18620-18631, SEP 2 2016. Web of Science Citations: 12.

BATISTA, FERNANDA A. H.; SERAPHIM, THIAGO V.; SANTOS, CLELTON A.; GONZAGA, MARISVANDA R.; BARBOSA, LEANDRO R. S.; RAMOS, CARLOS H. I.; BORGES, JULIO C. Low sequence identity but high structural and functional conservation: The case of Hsp70/Hsp90 organizing protein (Hop/Sti1) of Leishmania braziliensis. Archives of Biochemistry and Biophysics, v. 600, p. 12-22, JUN 15 2016. Web of Science Citations: 3.

DORES-SILVA, PAULO R.; BARBOSA, LEANDRO R. S.; RAMOS, CARLOS H. I.; BORGES, JULIO C. Human Mitochondrial Hsp70 (Mortalin): Shedding Light on ATPase Activity, Interaction with Adenosine Nucleotides, Solution Structure and Domain Organization. PLoS One, v. 10, n. 1 JAN 23 2015. Web of Science Citations: 17.

SERAPHIM, THIAGO V.; GAVA, LISANDRA M.; MOKRY, DAVID Z.; CAGLIARI, THIAGO C.; BARBOSA, LEANDRO R. S.; RAMOS, CARLOS H. I.; BORGES, JULIO C. The C-terminal region of the human p23 chaperone modulates its structure and function. Archives of Biochemistry and Biophysics, v. 565, p. 57-67, JAN 1 2015. Web of Science Citations: 7.

BATISTA, FERNANDA A. H.; ALMEIDA, GLESSLER S.; SERAPHIM, THIAGO V.; SILVA, KELLY P.; MURTA, SILVANE M. F.; BARBOSA, LEANDRO R. S.; BORGES, J. ULIO C. Identification of two p23 co-chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities. FEBS Journal, v. 282, n. 2, p. 388-406, JAN 2015. Web of Science Citations: 11.

ZANPHORLIN, LETICIA M.; ALVES, FEMANDA R.; RAMOS, CARLOS H. I. The effect of celastrol, a triterpene with antitumorigenic activity, on conformational and functional aspects of the human 90 kDa heat shock protein Hsp90 alpha, a chaperone implicated in the stabilization of the tumor phenotype. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1840, n. 10, p. 3145-3152, OCT 2014. Web of Science Citations: 16.

SERAPHIM, THIAGO V.; ALVES, MARINA M.; SILVA, INDJARA M.; GOMES, FRANCISCO E. R.; SILVA, KELLY P.; MURTA, SILVANE M. F.; BARBOSA, LEANDRO R. S.; BORGES, JULIO C. Low Resolution Structural Studies Indicate that the Activator of Hsp90 ATPase 1 (Aha1) of Leishmania braziliensis Has an Elongated Shape Which Allows Its Interaction with Both N- and M-Domains of Hsp90. PLoS One, v. 8, n. 6 JUN 24 2013. Web of Science Citations: 13.