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Title: Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis

Abstract

Here, 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.

Authors:
 [1];  [2];  [1];  [3];  [3];  [2]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States); Stony Brook Univ., Stony Brook, NY (United States)
  3. New York Univ. School of Medicine, New York, NY (United States)
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1257964
Report Number(s):
BNL-112309-2016-JA
Journal ID: ISSN 0027-8424
Grant/Contract Number:  
SC00112704
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 14; Journal ID: ISSN 0027-8424
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Mycobacterium tuberculosis; proteasome; proteasomal activator

Citation Formats

Bai, Lin, Hu, Kuan, Wang, Tong, Jastrab, Jordan B., Darwin, K. Heran, and Li, Huilin. Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis. United States: N. p., 2016. Web. doi:10.1073/pnas.1512094113.
Bai, Lin, Hu, Kuan, Wang, Tong, Jastrab, Jordan B., Darwin, K. Heran, & Li, Huilin. Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis. United States. https://doi.org/10.1073/pnas.1512094113
Bai, Lin, Hu, Kuan, Wang, Tong, Jastrab, Jordan B., Darwin, K. Heran, and Li, Huilin. Mon . "Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis". United States. https://doi.org/10.1073/pnas.1512094113. https://www.osti.gov/servlets/purl/1257964.
@article{osti_1257964,
title = {Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis},
author = {Bai, Lin and Hu, Kuan and Wang, Tong and Jastrab, Jordan B. and Darwin, K. Heran and Li, Huilin},
abstractNote = {Here, 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.},
doi = {10.1073/pnas.1512094113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 14,
volume = 113,
place = {United States},
year = {Mon Mar 21 00:00:00 EDT 2016},
month = {Mon Mar 21 00:00:00 EDT 2016}
}

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