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Title: Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion

Abstract

We report that Mycobacterium tuberculosis and Staphylococcus aureus secrete virulence factors via type VII protein secretion (T7S), a system that intriguingly requires all of its secretion substrates for activity. To gain insights into T7S function, we used structural approaches to guide studies of the putative translocase EccC, a unique enzyme with three ATPase domains, and its secretion substrate EsxB. The crystal structure of EccC revealed that the ATPase domains are joined by linker/pocket interactions that modulate its enzymatic activity. EsxB binds via its signal sequence to an empty pocket on the C-terminal ATPase domain, which is accompanied by an increase in ATPase activity. Surprisingly, substrate binding does not activate EccC allosterically but, rather, by stimulating its multimerization. Thus, the EsxB substrate is also an integral T7S component, illuminating a mechanism that helps to explain interdependence of substrates, and suggests a model in which binding of substrates modulates their coordinate release from the bacterium.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1392135
Alternate Identifier(s):
OSTI ID: 1178832
Grant/Contract Number:  
AC02-06CH11357; AC02-05CH11231; P41GM103393
Resource Type:
Journal Article: Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Name: Cell Journal Volume: 161 Journal Issue: 3; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Rosenberg, Oren S., Dovala, Dustin, Li, Xueming, Connolly, Lynn, Bendebury, Anastasia, Finer-Moore, Janet, Holton, James, Cheng, Yifan, Stroud, Robert M., and Cox, Jeffery S. Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion. United States: N. p., 2015. Web. doi:10.1016/j.cell.2015.03.040.
Rosenberg, Oren S., Dovala, Dustin, Li, Xueming, Connolly, Lynn, Bendebury, Anastasia, Finer-Moore, Janet, Holton, James, Cheng, Yifan, Stroud, Robert M., & Cox, Jeffery S. Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion. United States. https://doi.org/10.1016/j.cell.2015.03.040
Rosenberg, Oren S., Dovala, Dustin, Li, Xueming, Connolly, Lynn, Bendebury, Anastasia, Finer-Moore, Janet, Holton, James, Cheng, Yifan, Stroud, Robert M., and Cox, Jeffery S. 2015. "Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion". United States. https://doi.org/10.1016/j.cell.2015.03.040.
@article{osti_1392135,
title = {Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion},
author = {Rosenberg, Oren S. and Dovala, Dustin and Li, Xueming and Connolly, Lynn and Bendebury, Anastasia and Finer-Moore, Janet and Holton, James and Cheng, Yifan and Stroud, Robert M. and Cox, Jeffery S.},
abstractNote = {We report that Mycobacterium tuberculosis and Staphylococcus aureus secrete virulence factors via type VII protein secretion (T7S), a system that intriguingly requires all of its secretion substrates for activity. To gain insights into T7S function, we used structural approaches to guide studies of the putative translocase EccC, a unique enzyme with three ATPase domains, and its secretion substrate EsxB. The crystal structure of EccC revealed that the ATPase domains are joined by linker/pocket interactions that modulate its enzymatic activity. EsxB binds via its signal sequence to an empty pocket on the C-terminal ATPase domain, which is accompanied by an increase in ATPase activity. Surprisingly, substrate binding does not activate EccC allosterically but, rather, by stimulating its multimerization. Thus, the EsxB substrate is also an integral T7S component, illuminating a mechanism that helps to explain interdependence of substrates, and suggests a model in which binding of substrates modulates their coordinate release from the bacterium.},
doi = {10.1016/j.cell.2015.03.040},
url = {https://www.osti.gov/biblio/1392135}, journal = {Cell},
issn = {0092-8674},
number = 3,
volume = 161,
place = {United States},
year = {Wed Apr 01 00:00:00 EDT 2015},
month = {Wed Apr 01 00:00:00 EDT 2015}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at https://doi.org/10.1016/j.cell.2015.03.040

Citation Metrics:
Cited by: 83 works
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Works referencing / citing this record:

The type VII secretion system of Staphylococcus aureus secretes a nuclease toxin that targets competitor bacteria
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The Ess/Type VII secretion system of Staphylococcus aureus shows unexpected genetic diversity
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Structures of EccB1 and EccD1 from the core complex of the mycobacterial ESX-1 type VII secretion system
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Cas9+ conditionally-immortalized macrophages as a tool for bacterial pathogenesis and beyond
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The structure of the endogenous ESX-3 secretion system
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