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Conformational switching of the 26S proteasome enables substrate degradation

Mary E Matyskiela1, Gabriel C Lander, Andreas Martin

  • 1Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.

Nature Structural & Molecular Biology
|June 18, 2013
PubMed

Insights

The 26S proteasome

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Structural Biology

Background:

  • The 26S proteasome is a crucial ATP-dependent protease complex in eukaryotes.
  • It regulates protein homeostasis by degrading ubiquitinated substrates.
  • The precise mechanisms of substrate recognition, ubiquitination removal, and translocation are not fully understood.

Purpose of the Study:

  • To elucidate the structural mechanisms of the 26S proteasome during substrate degradation.
  • To visualize the conformational changes of the regulatory particle during substrate processing.
  • To understand the role of Rpn11 in substrate deubiquitination and translocation.

Main Methods:

  • Cryo-electron microscopy (Cryo-EM) was used to determine the structure of the 26S proteasome from Saccharomyces cerevisiae.
  • Structural analysis focused on the regulatory particle during substrate degradation.
  • Conformational states and molecular interactions were investigated.

Main Results:

  • The study reveals a switch in the regulatory particle from a preengaged to a translocation-competent conformation.
  • This translocation-competent state features a rearranged ATPase ring with uniform interfaces and a widened central channel.
  • The deubiquitinase Rpn11 shifts to a position facilitating simultaneous deubiquitination and translocation.

Conclusions:

  • The 26S proteasome undergoes significant conformational changes to facilitate substrate degradation.
  • The rearranged ATPase ring and Rpn11 positioning are key to efficient substrate processing.
  • This structural insight provides a mechanistic understanding of proteasomal degradation.

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