Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis

Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):E1983-92. doi: 10.1073/pnas.1512094113. Epub 2016 Mar 21.


The human pathogen Mycobacterium tuberculosis (Mtb) requires a proteasome system to cause lethal infections in mice. We recently found that proteasome accessory factor E (PafE, Rv3780) activates proteolysis by the Mtb proteasome independently of adenosine triphosphate (ATP). Moreover, PafE contributes to the heat-shock response and virulence of Mtb Here, we show that PafE subunits formed four-helix bundles similar to those of the eukaryotic ATP-independent proteasome activator subunits of PA26 and PA28. However, unlike any other known proteasome activator, PafE formed dodecamers with 12-fold symmetry, which required a glycine-XXX-glycine-XXX-glycine motif that is not found in previously described activators. Intriguingly, the truncation of the PafE carboxyl-terminus resulted in the robust binding of PafE rings to native proteasome core particles and substantially increased proteasomal activity, suggesting that the extended carboxyl-terminus of this cofactor confers suboptimal binding to the proteasome core particle. Collectively, our data show that proteasomal activation is not limited to hexameric ATPases in bacteria.

Keywords: Mycobacterium tuberculosis; X-ray crystallography; cryo-EM; proteasome; structural biology.

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / metabolism*
  • Crystallography, X-Ray
  • Heat-Shock Response
  • Humans
  • Mice
  • Mycobacterium tuberculosis / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits / metabolism*
  • Tuberculosis / microbiology
  • Tuberculosis / pathology*


  • Bacterial Proteins
  • PafE protein, Mycobacterium tuberculosis
  • Protein Subunits
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases

Associated data

  • PDB/5IET
  • PDB/5IEU