title: Plasmodium falciparum Hop: detailed analysis on complex formation with Hsp70 and Hsp90.
abstract: 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).
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, 6140 Grahamstown, South Africa.
authors.forename: Rowan
authors.initials: R
authors.lastname: Hatherley
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, 6140 Grahamstown, South Africa.
authors.forename: Crystal-Leigh
authors.initials: CL
authors.lastname: Clitheroe
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, 6140 Grahamstown, South Africa.
authors.forename: Ngonidzashe
authors.initials: N
authors.lastname: Faya
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, 6140 Grahamstown, South Africa. Electronic address: O.TastanBishop@ru.ac.za.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Tastan Bishop
mesh_terms: D000409:Alanine / Q000737:chemistry; D020816:Amino Acid Motifs; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018398:Homeodomain Proteins; D018832:Molecular Chaperones; D015800:Protozoan Proteins; D000409:Alanine
keywords: Co-chaperon; Homology modeling; Hsp70/Hsp90 organizing protein; Malaria; Protein–protein interaction