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    Structure-based prediction of Wnt binding affinities for Frizzled-type cysteine-rich domain

    253193.pdf (1.460Mb)
    Access Status
    Open access
    Authors
    Agostino, M.
    Öther-Gee Pohl, S.
    Dharmarajan, Arunasalam
    Date
    2017
    Type
    Journal Article
    
    Metadata
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    Citation
    Agostino, M. and Öther-Gee Pohl, S. and Dharmarajan, A. 2017. Structure-based prediction of Wnt binding affinities for Frizzled-type cysteine-rich domain. Journal of Biological Chemistry. 292 (27): Article ID 11218.
    Source Title
    Journal of Biological Chemistry
    DOI
    10.1074/jbc.M117.786269
    ISSN
    0021-9258
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/54450
    Collection
    • Curtin Research Publications
    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, pose 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 generate homology models of Wnt-Frizzled CRD interactions and develop 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 to 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.

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