Abstract
The prenyl‐protein chaperone PDEδ modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited. Small‐molecule inhibitors that target the PDEδ prenyl‐binding site have proven invaluable in the analysis of biological processes mediated by PDEδ, like KRas cellular trafficking. However, allosteric inhibitor release from PDEδ by the Arl2/3 GTPases limits their application. We describe the development of new proteolysis‐targeting chimeras (PROTACs) that efficiently and selectively reduce PDEδ levels in cells through induced proteasomal degradation. Application of the PDEδ PROTACs increased sterol regulatory element binding protein (SREBP)‐mediated gene expression of enzymes involved in lipid metabolism, which was accompanied by elevated levels of cholesterol precursors. This finding for the first time demonstrates that PDEδ function plays a role in the regulation of enzymes of the mevalonate pathway.
Highlights
The prenyl-protein chaperone PDEd modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited
We describe the development of new proteolysis-targeting chimeras (PROTACs) that efficiently and selectively reduce PDEd levels in cells through induced proteasomal degradation
Application of the PDEd PROTACs increased sterol regulatory element binding protein (SREBP)mediated gene expression of enzymes involved in lipid metabolism, which was accompanied by elevated levels of cholesterol precursors
Summary
International Edition: DOI: 10.1002/anie.201913904 German Edition: DOI: 10.1002/ange.201913904 Michael Winzker, Alexandra Friese, Uwe Koch, Petra Janning, Slava Ziegler, and Herbert Waldmann* Dedicated to Prof. Bernd Giese on the occasion of his 80th anniversary.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.