Structure and mechanism of the unique C2 domain of Aida

Axin interactor, dorsalization-associated (Aida) was identified as a regulatory factor that utilizes its C-terminal region to interact with axis formation inhibitor (Axin). Aida abrogates the Axin-mediated Jun N-terminal kinase activation required for proper dorsalization during zebrafish embryonic development, and thus functions as a proventralization factor. Here, we report the structure of Aida C-terminal fragments, which adopt a conventional C2 domain topology. We also demonstrate that Aida can specifically bind to phosphoinositides in a Ca(2+) -independent manner, and is able to associate with the cell membrane via a novel positively charged surface, namely a basic loop. Mutation of the positively charged patch on the basic loop leads to destabilization of the Aida-membrane association or disruption of the Aida-Axin interaction, resulting in impaired Jun N-terminal kinase inhibition. Together, our findings provide a molecular basis for C2 domain-mediated Aida-membrane and Aida-Axin associations.

The atomic coordinates and structure factors of the mouse Aida C2 domain (code: 2QZ5) and the zebrafish Aida C2 domain (code: 2QZQ) have been deposited in the Protein Data Bank (http://www.rcsb.org/)

AIDA physically interacts with Axin by anti tag coimmunoprecipitation (View interaction).