# Strategies for Post-Translational Control of Protein Expression and Their Applications
## 4 Conditional Control of Protein Stability Using Genetic Manipulation
### Light-Switchable Degrons  
Alternatively, degron activity can be controlled by light irradiation. The light oxygen voltage (LOV2) domain of phototropin consists of a flavin mononucleotide-binding core domain and the C-terminal J\(\alpha\)-helix. Blue light irradiation causes a covalent reaction between a cysteine of the core domain and the flavin mononucleotide (FMN), and induces a conformational change within the core. Then, the J\(\alpha\)-helix is unfolded and dissociated from the LOV2 domain (Figure 4a). The LOV2 domain technologies are based on the attachment of the degron sequence to the end of the Ja-helix, which can control protein activity by light. [PERSON] et al. developed a generic photosensitive degron by fusing the _Arabidopsis thaliana_ LOV2 domain of phototropin 1 to a degron derived from the murine ornithine decarboxylaselike degradation sequence (ODC) (Figure 4a) [64], which can be degraded by the 20S proteasome [65]. When the photosensitive degron is fused to the C terminus of a POI, the J\(\alpha\)-helix interacts with the LOV2 domain in the dark state, whereas blue light irradiation causes the C-terminal J\(\alpha\)-helix to dissociate from the LOV2 domain, thus revealing the ODC degron and inducing the degradation of the fusion protein. The [PERSON] group also developed a conditional blue light inducible degradation (B-LID) domain by fusing a mutant of the _Avena sativa_ LOV2 domain to a small peptide degron, RRRGN (Figure 4a) [66].  
[PERSON] et al. developed another optogenic system, named generalizable light-modulated protein stabilization system (GLIMPSe), using the Deadend (Dnd) protein, which is a degron derived from _Xenopus laevis_, in conjunction with two optogenetic modules; the light-inducible nuclear export system (LEXY), and evolved LOV (eLOV) (Figure 4b) [67]. The LEXY protein includes a nuclear localization signal (NLS), a TEV protease, a LOV2 domain, and a nuclear export signal (NES). In the dark state, the NLS dominates because of the caging of the NES; therefore, the LEXY protein is anchored into the nucleus. Similarly, the fusion protein containing the POI and TEV recognition sequence (TEVs) is processively degraded in the cytoplasm by the proteasome because of the degron activity of the Dnd protein. Blue light irradiation causes a conformational change in eLOV and facilitates its dissociation from the TEVs. Simultaneously, the NES in the LEXY protein in the nucleus is  
Figure 4: Light-switchable degrons. Concepts of (**a**) photosensitive degron and B-LID, (**b**) generalizable light-modulated protein stabilization system (GLIMPSe), and (**c**) small-molecule-dependent photolytic peptide.  
also uncaged, resulting in the export of this protein into the cytoplasm. The exposed TEV protease of the LEXY protein cleaves the TEVs, thus releasing the POI-elLOV fusion protein.  
[PERSON] et al. found that YM-53601, which is a small-molecule inhibitor of squalene synthase (SQS), selectively degrades SQS upon UV irradiation [68]. They demonstrated that the light-induced degradation of SQS requires its short C-terminal peptide. When the SQS peptide was fused to target proteins at either the N or C terminus, the fusion proteins were selectively degraded upon both YM-53601 and UV exposure. UV irradiation induces the homolytic C-O bond cleavage of YM-53601, which generates radical species and abstracts hydrogen atoms from the SQS peptide, thus resulting in the degradation of the fusion protein.