PHOTACs selectively degrade proteins under light control in hippocampus slices

We got together with the Trauner Lab to develop a CaMKIIalpha- PHOtochemically TArgeting Chimeras (PHOTACs). The goal was to test a new concept for degrading specific proteins with high spatial and temporal precision controlled by light. A PHOTAC is a small molecule that catalyzes ubiquitylation and degradation of a target protein through endogenous proteasomes when activated by wavelength-selective illumination. This proof of concept study targeted CaMKIIalpha because it is crucial for baseline synaptic function. We are busy developing and validating a set of PKMzeta-targeting PHOTACs.

The PHOTAC logic (left) and effect (right). A ligand to a protein of interest (POI) is attached to an E3 ligase ligand via a photo-sensitive linker. Wavelength-specific light switched the PHOTAC between the active and inactive state. In the active state the E3 ligase ligand is available to bind to endogenous E3 ligase and the POI (we targeted CaMKIIalpha) catalyzing ubquitylation of the POI and thus its proteosomal degradation. The CaMKII-PHOTAC effectively attenuated baseline perforate path synaptic function in hippocampal slices only when if the PHOTAC was illuminated.

Claudia Jou

Dr. Alejandro Grau-Perales