Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide

Abstract

Plasmodiumfalciparum FK506-binding protein 35 (PfFKBP35) that binds to FK506 contains a conserved tetratricopeptide repeat (TPR) domain. Several known TPR domains such asHop, PPP5, CHIP, and FKBP52 are structurally conserved and are able to interactwithmolecular chaperones such as Hsp70/Hsp90.Here, wepresent thecrystal structureofPfFKBP35-TPRanddemonstrate its interaction with Hsp90 C-terminal pentapeptide (MEEVD) by surface plasmon resonance and nuclear magnetic resonance spectroscopy-based binding studies.Our sequence and structural analyses reveal that PfFKBP35 is similar to Hop and PPP5 in possessing all the conserved residueswhich are important for carboxylate clampingwith Hsp90.Mutational studies were carried out on positively charged clamp residues that are crucial for binding to carboxylate groups of aspartate, showing that all the mutated residues are important for Hsp90 binding.Molecular docking and electrostatic calculations demonstrated that theMEEVD peptide ofHsp90 can form aspartate clampunlike FKBP52. Our results provide insightful information and structural basis about themolecular interaction between PfFKBP35-TPR and Hsp90. © 2009 The Protein Society.