Calmodulin binds to Drosophila TRP with an unexpected mode

Drosophila TRP is a calcium-permeable cation channel essential for fly visual signal transduction. During phototransduction, Ca2+ mediates both positive and negative feedback regulation on TRP channel activity, possibly via binding to calmodulin (CaM). However, the molecular mechanism underlying Ca2+ modulated CaM/TRP interaction is poorly understood. Here, we discover an unexpected, Ca2+-dependent binding mode between CaM and TRP. The TRP tail contains two CaM binding sites (CBS1 and CBS2) separated by an similar to 70-residue linker. CBS1 binds to the CaM N-lobe and CBS2 recognizes the CaM C-lobe. Structural studies reveal the lobe-specific binding of CaM to CBS1&2. Mutations introduced in both CBS1 and CBS2 eliminated CaM binding in full-length TRP, but surprisingly had no effect on the response to light under physiological conditions, suggesting alternative mechanisms governing Ca2+-mediated feedback on the channel activity. Finally, we discover that TRPC4, the closest mammalian paralog of Drosophila TRP, adopts a similar CaM binding mode.

Automated summary

A new calcium-dependent binding mode between calmodulin (CaM) and Drosophila TRP is discovered, with TRP tail containing two CaM binding sites and CaM showing lobe-specific binding to CBS1&2. Mutations in both CBS1 and CBS2 eliminated CaM binding in full-length TRP, but alternative mechanisms may govern the feedback on channel activity under physiological conditions. Additionally, the closest mammalian paralog of Drosophila TRP, TRPC4, adopts a similar CaM binding mode.