Protein degradation plays a central role in many cellular functions. Misfolded and damaged proteins are removed from the cell to avoid toxicity. The concentrations of regulatory proteins are adjusted by degradation at the appropriate time. Both foreign and native proteins are digested into small peptides as part of the adaptive immune response. In eukaryotic cells, an ATP-dependent protease called the proteasome is responsible for much of this proteolysis. Proteins are targeted for proteasomal degradation by a two-part degron, which consists of a proteasome binding signal and a degradation initiation site. Here we describe how both components contribute to the specificity of degradation.
The proteasome is the degradation machine at the center of the ubiquitin-proteasome system and controls the concentrations of many proteins in eukaryotes. It is highly processive so that substrates are degraded completely into small peptides, avoiding the formation of potentially toxic fragments. Nonetheless, some proteins are incompletely degraded, indicating the existence of factors that influence proteasomal processivity. We have quantified proteasomal processivity and determined the underlying rates of substrate degradation and release. We find that processivity increases with species complexity over a 5-fold range between yeast and mammalian proteasome, and the effect is due to slower but more persistent degradation by proteasomes from more complex organisms. A sequence stretch that has been implicated in causing incomplete degradation, the glycine-rich region of the NFκB subunit p105, reduces the proteasome’s ability to unfold its substrate, and polyglutamine repeats such as found in Huntington’s disease reduce the processivity of the proteasome in a length-dependent manner.
Background: Three Gli transcription factors mediate Hedgehog signaling. The proteasome remodels two Glis by degrading them only partially. Results: The extent of degradation is affected by three elements in Gli3: a folded structure, a linker, and a correctly spaced degron. Gli1 lacks two of them. Conclusion: A three-component signal determines whether Gli proteins are remodeled. Significance: These findings elucidate an unusual post-translational regulatory mechanism.
Summary
The ability to induce degradation of a protein of interest is a powerful experimental tool used to ascertain protein function. Iwamoto et al. (2010) describe a method that allows reversible and dose-dependent modulation of the stability of any target protein.
In the version of this article initially published, in Figure 3 the term "free energy" appears with the horizontal axes rather than the vertical axes of the energy diagrams. The error has been corrected in the HTML and PDF versions of the article.
954volume 5 number 12 december 2009 nature chemical biology co r r i g e n da a n d e r r ata
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