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Structural control for the coordinated assembly into functional pathogenic type-3 secretion systems

Nikolaus Goessweiner-Mohr, Vadim Kotov, Matthias J. Brunner, Julia Mayr, Jiri Wald, Lucas Kuhlen, Sean Miletic, Oliver Vesper, Wolfgang Lugmayr, Samuel Wagner, Frank DiMaio, Susan Lea, Thomas C. Marlovits
doi: https://doi.org/10.1101/714097
Nikolaus Goessweiner-Mohr
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Vadim Kotov
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
2Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Matthias J. Brunner
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Julia Mayr
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Jiri Wald
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
2Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Lucas Kuhlen
8Oxford University, Sir William Dunn School of Pathology, Oxford, United Kingdom
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Sean Miletic
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
2Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Oliver Vesper
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
2Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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Wolfgang Lugmayr
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
2Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany
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Samuel Wagner
6Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfried-Aulhorn-Str. 6, 72076 Tübingen, Germany
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Frank DiMaio
7University of Washington, Department of Biochemistry, Seattle, Washington, USA
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Susan Lea
8Oxford University, Sir William Dunn School of Pathology, Oxford, United Kingdom
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Thomas C. Marlovits
1University Medical Center Hamburg-Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
2Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany
3Deutsches Elektronen-Synchrotron Zentrum (DESY), Notkestrasse 85, D-22607 Hamburg, Germany
4Institute of Molecular Biotechnology GmbH (IMBA), Austrian Academy of Sciences, Dr Bohr-Gasse 5, A-1030 Vienna, Austria
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, A-1030 Vienna, Austria
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  • For correspondence: marlovits@marlovitslab.org
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Abstract

Functional injectisomes of the type-3 secretion system assemble into highly defined and stoichiometric bacterial molecular machines essential for infecting human and other eukaryotic cells. However, the mechanism that governs the regulated step-wise assembly process from the nucleation-phase, to ring-assembly, and the filamentous phase into a membrane embedded needle complex is unclear. We here report that the formation of a megadalton-sized needle complexes from Salmonella enterica serovar Typhimurium (SPI-1, Salmonella pathogenicity island-1) with proper stoichiometries is highly structurally controlled competing against the self-assembly propensity of injectisome components, leading to a highly unusual structurally-pleiotropic phenotype. The structure of the entire needle complex from pathogenic injectisomes was solved by cryo electron microscopy, focused refinements (2.5-4 Å) and co-variation analysis revealing an overall asymmetric arrangement containing cyclic, helical, and asymmetric sub-structures. The centrally located export apparatus assembles into a conical, pseudo-helical structure and provides a structural template that guides the formation of a 24-mer cyclic, surrounding ring, which then serves as a docking interface comprising three different conformations for sixteen N-terminal InvG subunits of the outer secretin ring. Unexpectedly, the secretin ring excludes the 16th protein chain at the C-terminal outer ring, resulting in a pleiotropic 16/15-mer ring and consequently to an overall 24:16/15 basal body structure. Finally, we report how the transition from the pseudo-helical export apparatus into the helical filament is structurally resolved to generate the protein secretion channel, which provides the structural basis to restrict access of unfolded effector substrates. These results highlight the diverse molecular signatures required for a highly coordinated assembly process and provide the molecular basis for understanding triggering and transport of unfolded proteins through injectisomes.

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Posted July 24, 2019.
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Structural control for the coordinated assembly into functional pathogenic type-3 secretion systems
Nikolaus Goessweiner-Mohr, Vadim Kotov, Matthias J. Brunner, Julia Mayr, Jiri Wald, Lucas Kuhlen, Sean Miletic, Oliver Vesper, Wolfgang Lugmayr, Samuel Wagner, Frank DiMaio, Susan Lea, Thomas C. Marlovits
bioRxiv 714097; doi: https://doi.org/10.1101/714097
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Structural control for the coordinated assembly into functional pathogenic type-3 secretion systems
Nikolaus Goessweiner-Mohr, Vadim Kotov, Matthias J. Brunner, Julia Mayr, Jiri Wald, Lucas Kuhlen, Sean Miletic, Oliver Vesper, Wolfgang Lugmayr, Samuel Wagner, Frank DiMaio, Susan Lea, Thomas C. Marlovits
bioRxiv 714097; doi: https://doi.org/10.1101/714097

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