2. Academic Validation
  3. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase

  • Nat Commun. 2019 Jan 10;10(1):131. doi: 10.1038/s41467-018-08027-7.
Blake E Smith 1,  Stephen L Wang 1,  Saul Jaime-Figueroa 1,  Alicia Harbin 2,  Jing Wang 2,  Brian D Hamman 2,  Craig M Crews 3 4 5
Affiliations

Affiliations

  • 1 Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA.
  • 2 Arvinas, Inc., 5 Science Park, New Haven, CT, 06511, USA.
  • 3 Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA. craig.crews@yale.edu.
  • 4 Department of Chemistry, Yale University, New Haven, CT, 06511, USA. craig.crews@yale.edu.
  • 5 Department of Pharmacology, Yale University, New Haven, CT, 06511, USA. craig.crews@yale.edu.
PMID: 30631068 DOI: 10.1038/s41467-018-08027-7
Abstract

PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin Ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related protein families remain elusive. Here, we generate isoform-selective PROTACs for the p38 MAPK Family using a single warhead (foretinib) and recruited E3 Ligase (von Hippel-Lindau). Based on their distinct linker attachments and lengths, these two PROTACs differentially recruit VHL, resulting in degradation of p38α or p38δ. We characterize the role of ternary complex formation in driving selectivity, showing that it is necessary, but insufficient, for PROTAC-induced substrate ubiquitination. Lastly, we explore the p38δ:PROTAC:VHL complex to explain the different selectivity profiles of these PROTACs. Our work attributes the selective degradation of two closely-related proteins using the same warhead and E3 Ligase to heretofore underappreciated aspects of the ternary complex model.

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