Kremen is beyond a subsidiary co-receptor of Wnt signaling: an in silico validation

Kremen-1 is a co-receptor of Wnt signaling, interacting with the Dkk-3 protein, which is an antagonist of the Wnt/beta catenin pathway. In the present study we attempted to shed some light on the possible orientations of Kremen/Dkk-3 interactions, explaining the mechanisms of Kremen and Dkk-3 functions. Employing state-of-the-art software, a Kremen model was built and subsequently refined. The quality of the final model was evaluated using RMSD calculations. Ultimately, we used the Kremen model for docking analysis between Kremen and Dkk-3 molecules. A model built by the Robetta server showed the best quality scores. Near native coordination of the final model was verified getting < 2 angstrom RMSD values between our model and an experimentally resolved structure. Docking analysis indicates that one low energy orientation for Kremen/Dkk-3 involves all extracellular domains of Kremen, while another only involves the CUB and WSC domains. Kremen receptors may determine either antitumor or protumor effects of the Dkk protein. Based on existing reports and our findings, we hypothesized that there could be different cellular fate outcomes due to the orientation of Kremen and Dkk-3 interactions. One orientation of the Kremen/Dkk complex could lead to Kringle mediated antitumor effects, while another could end with CUB mediated protumor effects.