Hsp70 is a major molecular chaperones and function as pivot receiving and distributing substrates from/to other molecular chaperones, both in the cytoplasm and in organelles. The mitochondrial Hsp70 (mtHsp70) is involved in the import of mitochondrial proteins produced in the cytoplasm and their subsequent folding, is essential for mitochondrial biogenesis. In mammals, the mtHsp70 is called mortalin due to its involvement in apoptosis and senescence. There is great interest in the mortalin study since it is overexpressed in tumor cells, which makes it as target for pharmacological inhibition, besides participating in the maintenance of various diseases caused by aging, such as Parkinson's and Alzheimer's. Although known for a long time, the production of recombinant human mortalin is limited due to a self-aggregation process which results in their recombinant production in aggregated form. Recently, a new mtHsp70 co-chaperone was described that operates assisting in the mtHsp70 correct folding. This mitochondrial protein is called Hep1 (Hsp70 escort protein 1) and allows the obtaining of recombinant mtHsp70 soluble and in the functional form. One goal of this project is the co-expression of human mortalin and Hep1 (hHep1) to enable the production of mortalin soluble as well as the structural and functional characterization of recombinant human mortalin. Objectives of this proposal are also the characterization of Leishmania braziliensis orthologue Hep1 (LbHep1) that has shown activity in maintaining human mortalin as well as mtHsp70 L. braziliensis (LbmtHsp70) in their soluble forms. From this study, it is expected (1) understanding the functional mechanism of the interaction with the Hep1 and mortalin and infer other possible functions for this protein. With getting the mortalin in the soluble form, is also expected (2) to obtain structural and functional information of this protein to enable compare it to cytoplasmic Hsp70. It is also expected (3) characterize the interaction of mortalin with its human nucleotide exchange factors (hGrpE) of mitochondrial origin, hGrpe # 1 and # 2. Regarding the protozoa systems, (4) the objective is to study in more detail the mechanism of interaction of LbHep1 with LbmtHsp70 , and ( 5 ) the operation of LbmtHsp70 comparing it to human mortalin. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
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;
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,
SEP 15 2019.
Web of Science Citations: 0.