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Title: The Legionella Effector SidC Defines a Unique Family of Ubiquitin Ligases Important for Bacterial Phagosomal Remodeling

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1162997
Report Number(s):
BNL-106943-2014-JA
Journal ID: ISSN 0027--8424
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 111; Journal Issue: 29
Country of Publication:
United States
Language:
English

Citation Formats

Hsu, F., Luo, X., Qiu, J., Teng, Y., Jin, J., Smolka, M., Luo, Z., and Mao, Y. The Legionella Effector SidC Defines a Unique Family of Ubiquitin Ligases Important for Bacterial Phagosomal Remodeling. United States: N. p., 2014. Web. doi:10.1073/pnas.1402605111.
Hsu, F., Luo, X., Qiu, J., Teng, Y., Jin, J., Smolka, M., Luo, Z., & Mao, Y. The Legionella Effector SidC Defines a Unique Family of Ubiquitin Ligases Important for Bacterial Phagosomal Remodeling. United States. doi:10.1073/pnas.1402605111.
Hsu, F., Luo, X., Qiu, J., Teng, Y., Jin, J., Smolka, M., Luo, Z., and Mao, Y. Tue . "The Legionella Effector SidC Defines a Unique Family of Ubiquitin Ligases Important for Bacterial Phagosomal Remodeling". United States. doi:10.1073/pnas.1402605111.
@article{osti_1162997,
title = {The Legionella Effector SidC Defines a Unique Family of Ubiquitin Ligases Important for Bacterial Phagosomal Remodeling},
author = {Hsu, F. and Luo, X. and Qiu, J. and Teng, Y. and Jin, J. and Smolka, M. and Luo, Z. and Mao, Y.},
abstractNote = {},
doi = {10.1073/pnas.1402605111},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 29,
volume = 111,
place = {United States},
year = {Tue Jul 22 00:00:00 EDT 2014},
month = {Tue Jul 22 00:00:00 EDT 2014}
}
  • Processes as diverse as receptor binding and signaling, cytoskeletal dynamics, and programmed cell death are manipulated by mimics of host proteins encoded by pathogenic bacteria. We show here that the Salmonella virulence factor SspH2 belongs to a growing class of bacterial effector proteins that harness and subvert the eukaryotic ubiquitination pathway. This virulence protein possesses ubiquitination activity that depends on a conserved cysteine residue. A crystal structure of SspH2 reveals a canonical leucine-rich repeat (LRR) domain that interacts with a unique E{sub 3} ligase [which we have termed NEL for Novel E{sub 3} Ligase] C-terminal fold unrelated to previously observedmore » HECT or RING-finger E{sub 3} ligases. Moreover, the LRR domain sequesters the catalytic cysteine residue contained in the NEL domain, and we suggest a mechanism for activation of the ligase requiring a substantial conformational change to release the catalytic domain for function. We also show that the N-terminal domain targets SspH2 to the apical plasma membrane of polarized epithelial cells and propose a model whereby binding of the LRR to proteins at the target site releases the ligase domain for site-specific function.« less
  • No abstract prepared.
  • Skp1–Cul1–F-box (SCF) E3 ligases play key roles in multiple cellular processes through ubiquitination and subsequent degradation of substrate proteins. Although Skp1 and Cul1 are invariant components of all SCF complexes, the 69 different human F-box proteins are variable substrate binding modules that determine specificity. SCF E3 ligases are activated in many cancers and inhibitors could have therapeutic potential. Here, we used phage display to develop specific ubiquitin-based inhibitors against two F-box proteins, Fbw7 and Fbw11. Unexpectedly, the ubiquitin variants bind at the interface of Skp1 and F-box proteins and inhibit ligase activity by preventing Cul1 binding to the same surface.more » Using structure-based design and phage display, we modified the initial inhibitors to generate broad-spectrum inhibitors that targeted many SCF ligases, or conversely, a highly specific inhibitor that discriminated between even the close homologs Fbw11 and Fbw1. We propose that most F-box proteins can be targeted by this approach for basic research and for potential cancer therapies.« less