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Characterization of the role of HSP70 system and HSP22 chaperone as a disaggregase complex in humans

Grant number: 16/03764-0
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): October 03, 2016
Effective date (End): October 02, 2017
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Carlos Henrique Inacio Ramos
Grantee:Conrado de Campos Gonçalves
Supervisor: Jason C. Young
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: McGill University, Montreal, Canada  
Associated to the scholarship:14/00076-0 - Study of important chaperone-interaction from the celular protein quality control system in higher eukaryotes., BP.DR


The chaperones of the Hsp70 family have central role in the cellular network of molecular chaperones. These chaperones are engaged in many biological processes, including the folding of recently synthesized proteins to the native state, prevention of aggregation, solubilization and refolding of misfolded or aggregated proteins and transport of proteins across membranes. Hsp70 generally depend on co-chaperones to regulate ATPase cycles and affinity for substrate, especially the J-domain proteins (Hsp40) and Hsp110, nucleotide exchange factors (NEF). Although the ATPase cycle of Hsp70 proteins is well known, structural information on the larger complexes formed by Hsp70, Hsp40 and client protein is still limited because of its transient nature. Apart from the lack of structural information about Hsp70 complexes, functional information is also scarce. Intracellular accumulation of protein aggregates is an important mark of stressed cells and can be a serious threat to the health of organisms, generally culminating in diverse neuro-degenerative disorders, such as Huntington's, Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis, which have no known cure yet. Despite metazoan cells lack the main disaggregase chaperone Hsp100, they still are able to eliminate protein aggregates. This issue was unresolved but, recently, protein disaggregation experiments using purified human and C. elegans components showed that interaction between class A and B J-proteins and Hsp70 with the NEF Hsp110 is the responsible for reactivate client aggregated after thermal stress. Specifically, class B DNAJB1 cooperated with class A DNAJA2 (or DNAJA1). In these findings, the disaggregase activity of Hsp70 system depends on the presence of a sHsp from yeast (Hsp26), however the mechanism by which these sHsps play a role in the process still needs to be studied in detail. Because of the importance of this system in protein quality control biology, the goal of this proposal is to investigate the disaggregase system in human molecular chaperones. For this, the objectives are: (1) establish a protocol for purification of human HspB8/Hsp22 and characterize its role in the disaggregation process in vitro; (2) investigate the role of Hsp22, as a potential partner of Hsp70/J-proteins/Hsp110, in disaggregation processes by performing experiments in cultured cells; (3) characterize the effect of J-proteins from class A (DJA4) and B (DJB4) on the activity of human Hsp70. (AU)

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Scientific publications
(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)
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, . (17/26131-5, 16/03764-0)
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., . (16/02137-1, 12/50161-8, 16/14503-2, 16/04246-2, 16/03764-0, 18/11948-9, 17/26131-5)

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