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

Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis.

Author information

1
Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973;
2
Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794;
3
Department of Microbiology, New York University School of Medicine, New York, NY 10016.
4
Department of Microbiology, New York University School of Medicine, New York, NY 10016 heran.darwin@med.nyu.edu hli@bnl.gov.
5
Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794; heran.darwin@med.nyu.edu hli@bnl.gov.

Abstract

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

PMID:
27001842
PMCID:
PMC4833279
DOI:
10.1073/pnas.1512094113
[Indexed for MEDLINE]
Free PMC Article

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