Abstract
Wnt signaling pathways are of significant interest in development and oncogenesis. The first step in these pathways typically involves the binding of a Wnt protein to the cysteine-rich domain (CRD) of a Frizzled receptor. Wnt-Frizzled interactions can be antagonized by secreted Frizzled-related proteins (SFRPs), which also contain a Frizzled-like CRD. The large number of Wnts, Frizzleds, and SFRPs, as well as the hydrophobic nature of Wnt, poses challenges to laboratory-based investigations of interactions involving Wnt. Here, utilizing structural knowledge of a representative Wnt-Frizzled CRD interaction, as well as experimentally determined binding affinities for a selection of Wnt-Frizzled CRD interactions, we generated homology models of Wnt-Frizzled CRD interactions and developed a quantitative structure-activity relationship for predicting their binding affinities. The derived model incorporates a small selection of terms derived from scoring functions used in protein-protein docking, as well as an energetic term considering the contribution made by the lipid of Wnt to the Wnt-Frizzled binding affinity. Validation with an external test set suggests that the model can accurately predict binding affinity for 75% of cases and that the error associated with the predictions is comparable with the experimental error. The model was applied to predict the binding affinities of the full range of mouse and human Wnt-Frizzled and Wnt-SFRP interactions, indicating trends in Wnt binding affinity for Frizzled and SFRP CRDs. The comprehensive predictions made in this study provide the basis for laboratory-based studies of previously unexplored Wnt-Frizzled and Wnt-SFRP interactions, which, in turn, may reveal further Wnt signaling pathways.
Highlights
We used a set of mouse Wnt-Fzd CRD binding affinities determined by BLI [27] to develop and validate our bindin
2.08 Ϯ 0.42 0.91 Ϯ 0.05 1.39 Ϯ 0.45 a Mean values Ϯ2 S.D. shown; data for individual complexes shown in supplemental Tables S5–S10. b TM-score and C␣ root-mean-squared deviation (RMSD) values calculated with respect to the XWnt8-mFzd8
The TM-score and the root-mean-squared deviation (RMSD) of the C␣ atoms of the models with respect to the XWnt8mFzd8 CRD complex structure (Protein Data Bank code 4F0A) [19], which was the template for all models, were calculated
Summary
2.08 Ϯ 0.42 0.91 Ϯ 0.05 1.39 Ϯ 0.45 a Mean values Ϯ2 S.D. shown; data for individual complexes shown in supplemental Tables S5–S10. b TM-score and C␣ RMSD values calculated with respect to the XWnt8-mFzd. 2.08 Ϯ 0.42 0.91 Ϯ 0.05 1.39 Ϯ 0.45 a Mean values Ϯ2 S.D. shown; data for individual complexes shown in supplemental Tables S5–S10. B TM-score and C␣ RMSD values calculated with respect to the XWnt8-mFzd. CRD complex (Protein Data Bank code 4F0A). The TM-score for an optimally overlaid structure compared with itself is 1; the RMSD for an optimally overlaid structure compared with itself is 0
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