Proteolysis is essential for the control of metabolic pathways and the cell cycle. Bacterial caseinolytic proteases (Clp) use peptidase components, such as ClpP, to degrade defective substrate proteins and to regulate cellular levels of stress-response proteins. To ensure selective degradation, access to the proteolytic chamber of the double–ring ClpP tetradecamer is controlled by a critical gating mechanism of the two axial pores. The binding of conserved loops of the Clp ATPase component of the protease or small molecules, such as acyldepsipeptide (ADEP), at peripheral ClpP ring sites, triggers axial pore opening through dramatic conformational transitions of flexible N-terminal loops between disordered conformations in the “closed” pore state and ordered hairpins in the “open” pore state. In this study, we probe the allosteric communication underlying these conformational changes by comparing residue–residue couplings in molecular dynamics simulations of each configuration. Both principal component and normal mode analyses highlight large-scale conformational changes in the N-terminal loop regions and smaller amplitude motions of the peptidase core. Community network analysis reveals a switch between intra- and inter-protomer coupling in the open–closed pore transition. Allosteric pathways that connect the ADEP binding sites to N-terminal loops are rewired in this transition, with shorter network paths in the open pore configuration supporting stronger intra- and inter-ring coupling. Structural perturbations, either through the removal of ADEP molecules or point mutations, alter the allosteric network to weaken the coupling.
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28 March 2023
Research Article|
March 27 2023
Allosteric communication in the gating mechanism for controlled protein degradation by the bacterial ClpP peptidase
Special Collection:
New Views of Allostery
Ashan Dayananda
;
Ashan Dayananda
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing)
1
Department of Chemistry, University of Cincinnati
, Cincinnati, Ohio 45221, USA
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T. S. Hayden Dennison;
T. S. Hayden Dennison
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization)
1
Department of Chemistry, University of Cincinnati
, Cincinnati, Ohio 45221, USA
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Hewafonsekage Yasan Y. Fonseka
;
Hewafonsekage Yasan Y. Fonseka
a)
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization)
1
Department of Chemistry, University of Cincinnati
, Cincinnati, Ohio 45221, USA
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Mohammad S. Avestan
;
Mohammad S. Avestan
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization)
1
Department of Chemistry, University of Cincinnati
, Cincinnati, Ohio 45221, USA
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Qi Wang;
Qi Wang
b)
(Conceptualization, Investigation, Methodology, Validation, Visualization)
1
Department of Chemistry, University of Cincinnati
, Cincinnati, Ohio 45221, USA
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Riina Tehver
;
Riina Tehver
b)
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing)
2
Department of Physics and Astronomy, Denison University
, Granville, Ohio 43023, USA
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George Stan
George Stan
c)
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing)
1
Department of Chemistry, University of Cincinnati
, Cincinnati, Ohio 45221, USA
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J. Chem. Phys. 158, 125101 (2023)
Article history
Received:
December 18 2022
Accepted:
March 07 2023
Citation
Ashan Dayananda, T. S. Hayden Dennison, Hewafonsekage Yasan Y. Fonseka, Mohammad S. Avestan, Qi Wang, Riina Tehver, George Stan; Allosteric communication in the gating mechanism for controlled protein degradation by the bacterial ClpP peptidase. J. Chem. Phys. 28 March 2023; 158 (12): 125101. https://doi.org/10.1063/5.0139184
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