title: Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide.
abstract: 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.
authors.affiliation: Nanyang Technological University, Singapore.
authors.forename: Reema
authors.initials: R
authors.lastname: Alag
authors.forename: Nagakumar
authors.initials: N
authors.lastname: Bharatham
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Tanya
authors.initials: T
authors.lastname: Hills
authors.forename: Amaravadhi
authors.initials: A
authors.lastname: Harikishore
authors.forename: Anissa Anindya
authors.initials: AA
authors.lastname: Widjaja
authors.forename: Susana Geifman
authors.initials: SG
authors.lastname: Shochat
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
mesh_terms: 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*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D010455:Peptides; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus
references.citation: Curr Top Med Chem. 2003;3(12):1348-57
references.pmid: 12871166
references.citation: Mol Cell. 2000 Oct;6(4):899-907
references.pmid: 11090627
references.citation: Malar J. 2003 Sep 15;2:30
references.pmid: 14514358
references.citation: Biochem Pharmacol. 1994 Aug 3;48(3):495-503
references.pmid: 7520696
references.citation: Protein Expr Purif. 2007 May;53(1):179-85
references.pmid: 17289400
references.citation: Mol Biochem Parasitol. 1994 Sep;67(1):157-70
references.pmid: 7838176
references.citation: Trends Biochem Sci. 1997 Mar;22(3):87-92
references.pmid: 9066258
references.citation: Cell Stress Chaperones. 1996 Dec;1(4):237-50
references.pmid: 9222609
references.citation: Eur J Biochem. 2000 Aug;267(16):5085-92
references.pmid: 10931191
references.citation: Cell Mol Life Sci. 1999 Mar;55(3):423-36
references.pmid: 10228556
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41
references.pmid: 11517324
references.citation: Mol Biochem Parasitol. 2005 Jun;141(2):163-73
references.pmid: 15850699
references.citation: Structure. 2001 May 9;9(5):431-8
references.pmid: 11377203
references.citation: Brief Bioinform. 2004 Dec;5(4):378-88
references.pmid: 15606974
references.citation: Mol Biochem Parasitol. 2005 Feb;139(2):185-95
references.pmid: 15664653
references.citation: Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
references.pmid: 12563018
references.citation: J Biol Chem. 2002 Oct 25;277(43):40799-809
references.pmid: 12145316
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W665-7
references.pmid: 15215472
references.citation: J Mol Recognit. 1995 Jan-Apr;8(1-2):125-31
references.pmid: 7541226
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:297-326
references.pmid: 9131255
references.citation: J Mol Biol. 1997 Apr 4;267(3):727-48
references.pmid: 9126849
references.citation: Nat Struct Biol. 2000 Dec;7(12):1091-5
references.pmid: 11101887
references.citation: Cell. 2000 Mar 3;100(5):551-60
references.pmid: 10721992
references.citation: J Cell Physiol. 2001 Sep;188(3):281-90
references.pmid: 11473354
references.citation: Crit Rev Biochem Mol Biol. 2004 Sep-Dec;39(5-6):279-95
references.pmid: 15763706
references.citation: EMBO J. 1998 Mar 2;17(5):1192-9
references.pmid: 9482716
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Aug;62(Pt 8):859-66
references.pmid: 16855301
references.citation: Mol Biochem Parasitol. 2007 Jan;151(1):100-10
references.pmid: 17125854
references.citation: Curr Top Med Chem. 2003;3(12):1315-47
references.pmid: 12871165
references.citation: Proteins. 2008 Jan 1;70(1):300-2
references.pmid: 17876830
references.citation: Microbes Infect. 2002 Feb;4(2):165-74
references.pmid: 11880048
references.citation: Biochemistry. 2008 Jun 3;47(22):5951-61
references.pmid: 18465874
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8348-53
references.pmid: 15159550
references.citation: Cell. 2000 Apr 14;101(2):199-210
references.pmid: 10786835
references.citation: Structure. 2006 Mar;14(3):415-26
references.pmid: 16531226