Plasmodium falciparum Hop: detailed analysis on complex formation with Hsp70 and Hsp90
- Authors: Hatherley, Rowan , Clitheroe, Crystal-Leigh , Faya, Ngonidzashe , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125708 , vital:35810 , https://doi.10.1016/j.bbrc.2014.11.103
- Description: The heat shock organizing protein (Hop) is important in modulating the activity and co-interaction of two chaperones: heat shock protein 70 and 90 (Hsp70 and Hsp90). Recent research suggested that Plasmodium falciparum Hop (PfHop), PfHsp70 and PfHsp90 form a complex in the trophozoite infective stage. However, there has been little computational research on the malarial Hop protein in complex with other malarial Hsps. Using in silico characterization of the protein, this work showed that individual domains of Hop are evolving at different rates within the protein. Differences between human Hop (HsHop) and PfHop were identified by motif analysis. Homology modeling of PfHop and HsHop in complex with their own cytosolic Hsp90 and Hsp70 C-terminal peptide partners indicated excellent conservation of the Hop concave TPR sites bound to the C-terminal motifs of partner proteins. Further, we analyzed additional binding sites between Hop and Hsp90, and showed, for the first time, that they are distinctly less conserved between human and malaria parasite. These sites are located on the convex surface of Hop TPR2, and involved in interactions with the Hsp90 middle domain. Since the convex sites are less conserved than the concave sites, it makes their potential for malarial inhibitor design extremely attractive (as opposed to the concave sites which have been the focus of previous efforts).
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A step forward in defining Hsp90s as potential drug targets for human parasitic diseases
- Authors: Faya, Ngonidzashe
- Date: 2014
- Subjects: Heat shock proteins -- Research , Malaria -- Chemotherapy -- Research , Antimalarials -- Development -- Research , Parasitic diseases -- Research , Plasmodium
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4110 , http://hdl.handle.net/10962/d1012993
- Description: Parasitic diseases remain a health burden affecting more than 500 million people worldwide with malaria having the highest mortality rate. The parasites can be transferred to the human bodies either through the mouth by ingestion of contaminated food and water or through the skin by bug bites or direct contact to environments harbouring them. Epidemiological control seems to be impossible since there is failure to control the insect vectors as well as practice of hygiene. Therefore, this has led to the development of a number of vaccines, chemotherapy and disease control programs. However, parasites have increasingly developed resistance to traditionally used anti-parasitic drugs and due to that fact there is need for alternative medication for parasitic diseases. Heat shock protein 90 (Hsp90) facilitates the folding of proteins in all living cells and their role is more important to parasites because of their environmental changes, from vector to host. Hsp90s play a major role; therefore this justifies the need for a deeper analysis of the parasitic Hsp90s. Recent studies have revealed that, the Plasmodium sp. Hsp90 has an extended linker region which increases the protein’s affinity for ATP and its inhibitors. Therefore we hypothesize that there are also significant features in other parasitic Hsp90s which would lead to Hsp90 being defined as potential drug targets. In the present study an attempt was made to gain more insight into the differences in primary structure of human and parasitic Hsp90s. The sequences were retrieved from the NCBI database and analysis was done in three groups basing on the localization of the Hsp90. The physicochemical properties were calculated and in every group, the protozoan Hsp90s showed significant differences when compared to the human orthologs. Multiple sequence alignments (MSA) showed that endoplasmic reticulum Hsp90s have an extended region in the middle domain indicating their ability to bind to a unique subset of client proteins. Sequence identities between the human and parasites showed that the protozoan Hsp90s are less related to the human Hsp90s as compared to the other parasites. Likewise, motif analysis showed the trypanosomatids and apicomplexan groups have their own unique set of motifs and they were grouped together in the phylogenetic analysis. Phylogenetic analysis also showed that, the protozoan Hsp90s forms their own clades in each group while the helminths did not form in endoplasmic reticulum group. In this study, we concluded that, Hsp90 can be a potential drug target for the protozoan species and more specifically those from the apicomplexan and trypanosomatids groups.
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