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
The maintenance of protein homeostasis is critical for cellular survival, and molecular chaperones are essential for this process. One important protein for facilitating refolding is Hsp90, which also has key roles in a host of other cellular functions, such as proteostasis, epigenetics, telomere maintenance, innate immunity, and biological signaling, among others. Hence, disruption of Hsp90 function can have dramatic, if not lethal, consequences on the organism. One example of this includes the fact that several types of cancer are dependent on upregulated Hsp90 activity, making it an important drug target. Furthermore, interfering with Hsp90 activity has recently become a goal in the design of anti-parasitic agents. Interestingly, some protozoans, such as Leishmania braziliensis, contain two forms of p23, an Hsp90 co-chaperone and modulator of Hsp90 function. Likewise, the human ortholog of p23 can undergo caspase cleavage to P18, which has a completely different function than P23, and has been implicated in apoptosis. Lastly, some Hsp90 co-chaperones have been found to interact with Hsp104, and we propose that this could be conserved in higher eukaryotes. This project aims to further investigate Hsp90 interactions by 1) characterizing human and Leishmania braziliensis p23 protein variants using yeast as a surrogate expression system to measure in vivo activity, 2) further studies to establish an Hsp104-like protein activity in metazoans (ClpB homolog) by determining how its heterologous expression in yeast effects a panel of insoluble aggregate forming proteins, and 3) using yeast as an expression system to purify the human ClpB homolog in order to perform in vitro biochemical activity assays. These studies will significantly contribute to the current knowledge of human chaperone function, and are relevant to the parent project theme of Hsp90.
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