Amazing @led3hub.bsky.social Lecture by @thewoolab.bsky.social! She talked about her group's exciting work on protein C-terminal cyclic imids as natural ligands of cereblon for protein degradation. (1/3)
www.nature.com/articles/s41...

#TPD #DrugDiscovery #ChemBio #ChemSky #Degron

How short can a degron be?
A compact, genetically encoded, 9-aa tunable degron that drives MDM2-dependent degradation enabling precise control of protein levels from yeast to human cells.
Thanks to @eswarappalab.bsky.social for the opportunity to explore this in yeast.
#Degron #Yeast #CellBiology 🧬

Endogenous GFP-tagging of pmm2 does not interfere with Pmm2 function in medaka. (A) Schematic representation of the medaka pmm2 gene locus. Endogenous GFP knock-in outline at the C-terminus of the pmm2 coding sequence via CRISPR/Cas9 (scissors) and biotinylated (red stop signs) donor template [coding sequence, red boxes; untranslated region (UTR), white boxes]. Single copy integration by homology directed repair (HDR) with the right homology flank (RH) and a non-homologous end-joining (NHEJ) event of the left homology flank (LH). Transcript analysis revealed correctly spliced pmm2-GFP mRNA. (B) Representative hatchling homozygous for pmm2-GFP shows ubiquitous GFP expression and proper development.

@kpakari.bsky.social & co recapitulate the activity levels of hypomorphic mutations associated with human PMM2-congenital disorders of glycosylation in medaka. 🐟
doi.org/10.1242/bio....

#Degron #EndogenousGFPtagging #CRISPR

1️⃣ Mechanism & protein engineering:

Through circular permutation + degron masking, we designd dMCP & dPCP to be rapidly degraded unless bound to their cognate #RNA hairpins (MS2 & PP7). Hairpin binding switches them from unstable to bright, RNA-bound reporters via a #degron masking mechanism.

Context is everything! (N-) #degron specificity of a #ubiquitin ligase reprogrammed under #proteotoxic stress. Interesting implications for biology, drug design and how we assess E3 specificity....