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Human mortalin: interaction with liposomes, mitochondrion membrane, beta-amyloids and effect of its presence in the toxicity of beta-amyloids on neurons

Grant number: 16/22477-1
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): May 01, 2017
Effective date (End): April 30, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Julio Cesar Borges
Grantee:Paulo Roberto das Dores da Silva
Supervisor abroad: Antonio de Maio
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Local de pesquisa : University of California, San Diego (UC San Diego), United States  
Associated to the scholarship:14/16646-0 - Human mortalin: interaction with co-chaperones, p53 and mutants, aggregation kinectics, regulation/modulation and vesicle secretion, BP.PD

Abstract

Heat shock proteins (Hsps) are important components of the cellular chaperone pool, playing an important role in the protein folding, intracellular traffic, degradation and assisting proteins to obtain their native structure, etc. Having around 40-60% of identity among its prokaryotic and eukaryotic members, the Hsp70 superfamily corresponds to a family of proteins highly conserved. In humans there are four protein expressed, Hsp70 is stress inducible, whereas Hsc70, BIP and mtHsp70 are constitutively expressed. Prior studies have shown that human Hsp70s family has an unusual capacity of interacting with lipid membranes, and that this interaction is different between Hsc70 and Hsp70. Moreover, Hsps has been found on the surface of tumor cells and it has been shown that exogenous addition of Hsp70 to a variety of cells resulted in particular responses, which may occur after binding to the plasma membrane. In addition, Hsc70 and Hsp70 when incorporated into artificial membranes, are able to form a nucleotide-regulated ion-conducting channel (Arispe and De Maio, 2000, Vega et.al. 2008). Thus, these finds suggest that Hsp70s possess specific affinity for lipids, and that this interaction could be important to cell, perhaps, working as a form of communication during injury, infection and/or cell damage. The human mitochondrial Hsp70 (called mtHsp70 or mortalin) is involved in many cellular processes, including the import of proteins from the cytosol into the mitochondrion matrix. mtHsp70/mortalin could also be present in the cytoplasm where it is involved in the p53 sequestration, which is related to the proliferation of some cancers. The presence of mtHsp70/mortalin also participates in various aging diseases, such as Parkinson's and Alzheimer's. We hypothesize that mtHsp70/mortalin can also interact with the mitochondrion membrane. Moreover, we propose that the capacity of mtHsp70/mortalin to associate with membranes is important in the transport of cytosolic proteins into the mitochondria matrix. To test this hypothesis, we propose here to study the interaction of recombinant mtHsp70/mortalin with liposomes made of several lipids, using a well-established liposome insertion assay developed in the De Maio laboratory, in the presence and the absence of ligands. These studies will be complemented with liposomes, resembling the composition of the mitochondria membrane. We will also use the mitochondria membrane, which will be isolated and tested for the insertion of mtHsp70/mortalin. The second part of this proposal will be an investigation to study whether or not mtHsp70/mortalin facilitates the translocation of cytosolic proteins that are transported inside the mitochondria. Furthermore, mtHsp70/mortalin oligomerizes into high molecular weight complexes here called higher-order oligomer. We will investigate the aggregation process and seek for co-chaperones that revert this process and study if these higher-order oligomers have any function on the cell, since our test indicates they have secondary/tertiary structures and ATPase activity. We will also investigate the interaction of mtHsp70/mortalin monomers and oligomers with ²-amyloids and neurons. (AU)