Molecular interactions of PfHop as a target for anti-malarial drug development

• Applicant: Professor Dr. Klaus Lingelbach (†)
• Co-Applicants: Dr. Aileen Boshoff; Professor Dr. Heinrich Carl Hoppe; Professor Addmore Shonhai, Ph.D.
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 215044407

Heat shock protein 70 (Hsp70) and Hsp90 are some of the most studied molecular chaperones, proteins which themselves are responsible for the folding of other proteins in the cell. Hsp70 binds non-native proteins whilst substrates of Hsp90 are usually in native-like forms (Wegele et al., 2006). Proteins that require both Hsp70 and Hsp90 to fold are thus transferred from Hsp70 to Hsp90 during the folding process. Eukaryotic Hsp90 participates in the conformational regulation of signal transduction molecules, such as tyrosine kinases and steroid hormone receptors. For example, steroid hormone receptors associate with Hsp90 in order for them to adopt conformational competence for hormone binding (Dittmar and Pratt, 1997). In eukaryotes, the essential interaction between Hsp70 and Hsp90 is mediated by the Hsp70-Hsp90 Organising Protein, HOP (Nicolet and Craig, 1989). Both Hsp70 and Hsp90 possess C-terminally located EEVD motifs that interact with Hop via its tetratricopeptide repeat (TPR) domains, TPR1 and TPR2A motifs, respectively (Scheufler et al., 2000). It is most likely that the Hsp70-Hsp90 functional partnership in Plasmodium spp. facilitates the folding of key proteins in the parasite cell, particularly those involved in signal transduction. PfHsp90 is known to play an essential role in the survival of the parasite and the antibiotic geldanamycin is known to inhibit its function (Banumathy et al., 2003). In the previous funding period, we have studied PfHsp70-1, with a view to its possible usage as a drug target. Having fulfilled many of the targets we set for the initial funding period, in the next funding period, we wish to study the importance of PfHop for survival of the parasite. We suggest that, due to its highly important role in choreographing chaperone/chaperone interactions, PfHop and its interaction with other chaperones, may represent an ideal target for drug development.

• DFG Programme: Research Grants
• International Connection: South Africa
• Participating Person: Professor Dr. Jude Marek Przyborski