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Targeted destruction

  • Jonathan B Weitzman
Genome Biology20012:spotlight-20010724-01

https://doi.org/10.1186/gb-spotlight-20010724-01

Published: 24 July 2001

Keywords

MethionineUbiquitin LigaseLysine ResidueChimeric ProteinAngiogenesis Inhibitor

Ubiquitination targets proteins for degradation by the sequential attachment of ubiquitin to lysine residues within the substrate molecule. Target specificity is determined by the E3 ubiquitin-protein ligases. One class of E3s consists of the heterotetrameric Skp1-Cullin-F box (SCF) complexes. The mammalian F-box protein β-TRCP directs the degradation of IκBα by binding to a phosphorylated decapeptide site within the IκBα molecule.

In the July 17 Proceedings of the National Academy of Sciences, Sakamoto et al. describe a method for artificially controlling protein degradation by exploiting characteristics of the SCFβ-TRCP ubiquitin ligase (Proc Natl Acad Sci USA 2001, 98:8554-8559). To test the system they chose to target the methionine aminopeptidase (MetAP-2) protein which is bound by the angiogenesis inhibitor ovalicin (OVA). They synthesized an artificial compound called Protac-1 (proteolysis-targeting chimeric protein 1) which contained the IκBα phosphopeptide fused to ovalicin. They showed that Protac-1 can bind to MetAP-2 via the OVA moiety, and recruit it to the SCFβ-TRCP complex, leading to its ubiquitination and subsequent degradation by the proteosome. The authors suggest that synthetic Protacs will serve as useful research tools and therapeutic agents to target ubiquitin-dependent degradation of a chosen target protein.

References

  1. Ubiquitin-mediated proteolysis: biological regulation via destruction.Google Scholar
  2. SCF and Cullin/Ring H2-based ubiquitin ligasesGoogle Scholar
  3. Proceedings of the National Academy of Sciences , [http://www.pnas.org]
  4. Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2.Google Scholar

Copyright

© BioMed Central Ltd 2001

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