Docking of Fatty Acids into the WIF Domain of the Human Wnt Inhibitory Factor-1

Abstract

Palmitoylated Wnt proteins comprise a conserved family of secreted signaling molecules associated with variety of human cancers. WIF domain of the human WIF (Wnt inhibitory factor)-1 is sufficient for Wnt binding and signaling inhibition. Detailed interactions between Wnt and WIF-1 are not known. Computational docking was employed to identify a possible fatty acid binding site in the WIF domain. A putative binding site was identified inside the domain. WIF domain exhibited the highest affinity for C16:0–C18:0 (−22 kJ/mol free energy of binding) fatty acids. The results suggest a role of the WIF domain as a palmitoyl binding domain required for WIF-1 binding to palmitoylated Wnt and signaling inhibition.

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Correspondence to Tomas Malinauskas.

Electronic Supplementary Material

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Docking of palmitic acid into 20 conformers (from 2D3J PDB file) of the WIF domain. RMSD of five palmitic acid conformers exhibiting lowest DGbinding was evaluated as follows: (1) conformer exhibiting the lowest DGbinding was selected, (2) each of remaining four conformers was aligned with it and RMSD calculated using program PyMOL 1.0r1 (DeLano Scientific, USA), (3) mean derived from four RMSD values is presented in the graph. Non polar hydrogen atoms of fatty acids were not used for RMSD evaluation. (TIF 57 kb)

Variation of DGbinding between the WIF domain and saturated fatty acids. White circles represent average DGbinding values derived from five fatty acid conformers exhibiting the lowest free energy of binding as in Fig. 3. The colored contour graph is based on 100 DGbinding values that represent all fatty acid conformers generated during docking experiments. Violet colored regions represent frequently (>40 %, an inset) observed DGbinding values for particular fatty acid, for example, all C8:0 conformers docked into WIF domain with DGbinding values in the interval -12 to -15 kJ/mol. In contrast, only three C22:0 conformers out of 100 exhibited DGbinding values below -17 kJ/mol (red colored region).(TIF 3300 kb)

RMSD evaluation of five saturated fatty acid conformers exhibiting the lowest DGbinding. Mean RMSD values were derived as described below Suppl. Fig. 1. An inset represents RMSD evaluation of five unsaturated fatty acid conformers.(TIF 61 kb)

Complex (PDB 38 kb)

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Malinauskas, T. Docking of Fatty Acids into the WIF Domain of the Human Wnt Inhibitory Factor-1. Lipids 43, 227–230 (2008). https://doi.org/10.1007/s11745-007-3144-3

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Keywords

  • Wnt inhibitory factor-1
  • WIF domain
  • Wnt
  • Lipoprotein
  • Signaling
  • Palmitoylation
  • Docking
  • Fatty acids
  • Cancer