Crystal structure of dimeric FabZ of Plasmodium falciparum reveals conformational switching to active hexamers by peptide flips

Crystal structure of dimeric FabZ of Plasmodium falciparum reveals conformational switching to active hexamers by peptide flips
Received 15 February 2006; revised 21 March 2006; accepted 4 April 2006. Available online 21 April 2006.
Edited by Irmgard Sinning
P. Lakshmi Swarnamukhia, Shailendra Kumar Sharmaa, Preeti Bajaja, Namita Suroliab, Avadhesha Suroliaa and Kaza Sugunaa, ,
FEBS Letters
Article in Press
aMolecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
bJawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560 056, India
The crystal structure of ?-hydroxyacyl acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) has been determined at a resolution of 2.4 . PfFabZ has been found to exist as a homodimer (d-PfFabZ) in the crystals of the present study in contrast to the reported hexameric form (h-PfFabZ) which is a trimer of dimers crystallized in a different condition. The catalytic sites of this enzyme are located in deep narrow tunnel-shaped pockets formed at the dimer interface. A histidine residue from one subunit of the dimer and a glutamate residue from the other subunit lining the tunnel form the catalytic dyad in the reported crystal structures. While the position of glutamate remains unaltered in the crystal structure of d-PfFabZ compared to that in h-PfFabZ, the histidine residue takes up an entirely different conformation and moves away from the tunnel leading to a His-Phe cisÒtrans peptide flip at the histidine residue. In addition, a loop in the vicinity has been observed to undergo a similar flip at a TyrÒPro peptide bond. These alterations not only prevent the formation of a hexamer but also distort the active site geometry resulting in a dimeric form of FabZ that is incapable of substrate binding. The dimeric state and an altered catalytic site architecture make d-PfFabZ distinctly different from the FabZ structures described so far. Dynamic light scattering and size exclusion chromatographic studies clearly indicate a pH-related switching of the dimers to active hexamers.
Keywords: Fatty acid biosynthesis; ?-Hydroxyacyl ACP dehydratase; Crystal structure; Conformational switching; Peptide flip; Plasmodium falciparum
Abbreviations: FabZ, ?-hydroxyacyl ACP dehydratase; PfFabZ, FabZ from Plasmodium falciparum; d-PfFabZ, dimeric form of FabZ from Plasmodium falciparum; h-PfFabZ, hexameric form of FabZ from Plasmodium falciparum; PaFabZ, FabZ from Pseudomonas Aeruginosa; ACP, acyl carrier protein; FabA, ?-hydroxydecanoyl ACP dehydratase; EcFabA, FabA from Escherichia coli; DLS, dynamic light scattering; RH, hydrodynamic radius

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