Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide.
Plasmodium falciparum FK506-binding protein 35 (PfFKBP35) that binds to FK506 contains a conserved tetratricopeptide repeat (TPR) domain. Several known TPR domains such as Hop, PPP5, CHIP, and FKBP52 are structurally conserved and are able to interact with molecular chaperones such as Hsp70/Hsp90. Here, we present the crystal structure of PfFKBP35-TPR and demonstrate 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 residues which are important for carboxylate clamping with 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 the MEEVD peptide of Hsp90 can form aspartate clamp unlike FKBP52. Our results provide insightful information and structural basis about the molecular interaction between PfFKBP35-TPR and Hsp90.
Alag
Reema
R
Nanyang Technological University, Singapore.
Bharatham
Nagakumar
N
Dong
Aiping
A
Hills
Tanya
T
Harikishore
Amaravadhi
A
Widjaja
Anissa Anindya
AA
Shochat
Susana Geifman
SG
Hui
Raymond
R
Yoon
Ho Sup
HS
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D016415:Sequence Alignment; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D010455:Peptides; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus
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