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Structures of the multi-domain oxygen sensor DosP: remote control of a c-di-GMP phosphodiesterase by a regulatory PAS domain.

ABSTRACT: The heme-based direct oxygen sensor DosP degrades c-di-GMP, a second messenger nearly unique to bacteria. In stationary phase Escherichia coli, DosP is the most abundant c-di-GMP phosphodiesterase. Ligation of O₂ to a heme-binding PAS domain (hPAS) of the protein enhances the phosphodiesterase through an allosteric mechanism that has remained elusive. We determined six structures of full-length DosP in its aerobic or anaerobic conformations, with or without c-di-GMP. DosP is an elongated dimer with the regulatory heme and phosphodiesterase separated by nearly 180 Å. In the absence of substrate, regardless of the heme status, DosP presents an equilibrium of two distinct conformations. Binding of substrate induces DosP to adopt a single, ON-state or OFF-state conformation depending on its heme status. Structural and biochemical studies of this multi-domain sensor and its mutants provide insights into signal regulation of second-messenger levels.

SUBMITTER: Wu W

PROVIDER: S-EPMC11291140 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Structures of the multi-domain oxygen sensor DosP: remote control of a c-di-GMP phosphodiesterase by a regulatory PAS domain.

Wu Wenbi W Kumar Pankaj P Brautigam Chad A CA Tso Shih-Chia SC Baniasadi Hamid R HR Kober Daniel L DL Gilles-Gonzalez Marie-Alda MA

bioRxiv : the preprint server for biology 20240724

The heme-based direct oxygen sensor DosP degrades c-di-GMP, a second messenger nearly unique to bacteria. In stationary phase <i>Escherichia coli</i>, DosP is the most abundant c-di-GMP phosphodiesterase. Ligation of O<sub>2</sub> to a heme-binding PAS domain (hPAS) of the protein enhances the phosphodiesterase through an allosteric mechanism that has remained elusive. We determined six structures of full-length DosP in its aerobic or anaerobic conformations, with or without c-di-GMP. DosP is an ...[more]

PMID: 39091779

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Project description:Periodontal disease (PD) results from a shift in the composition of the microbial community of the subgingival crevice. As the bacterial population transitions from Gram-positive bacteria to predominantly Gram-negative anaerobes and spirochetes, dramatic changes occur in the physiological and immunological environment at diseased sites. Treponema denticola thrives in periodontal pockets, indicating that it has a unique ability to adapt to changing environmental conditions. Hpk2 (tde1970), a Per-Arnt-Sim motif (PAS) domain-containing histidine kinase (HK), is part of the T. denticola Hpk2-Rrp2 (tde1969) two-component regulatory (TCR) system. This TCR system is growth phase regulated and has been postulated to play a key role in adaptive responses. In this study, we employ predictive structural analyses and site-directed mutagenesis to investigate the functional role of specific amino acid residues located within the Hpk2 PAS domain. Specific substitutions impacted autophosphorylation (AP), phosphotransfer (PT), oligomerization, and hemin binding. The AP, PT, hemin binding, and oligomerization potential of some mutated Hpk2 proteins differed under aerobic versus anaerobic reaction conditions. The data presented here suggest that the regulatory activity of Hpk2 is linked to diatomic gas levels. In a broader sense, this study highlights the importance of studying proteins produced by anaerobes under conditions that approximate the environment in which they thrive.IMPORTANCE Periodontal disease affects nearly 60% of the global adult population. Its costs to individuals, and to society as a whole, are enormous. As periodontal disease develops, there is a shift in the composition of the oral microbial community. The bacteria that become dominant are able to cause significant damage to the tissues that support the teeth, leading to tooth loss. Treponema denticola is one of the keystone pathogens associated with periodontal disease. An earlier study demonstrated that the Hpk2 and Rrp2 proteins play an important role in adaptive responses. Here, we explore the role of specific Hpk2 amino acids in environmental sensing and function, using structural analyses and site-directed mutagenesis.

Dataset Information

Structures of the multi-domain oxygen sensor DosP: remote control of a c-di-GMP phosphodiesterase by a regulatory PAS domain.

Publications

Structures of the multi-domain oxygen sensor DosP: remote control of a c-di-GMP phosphodiesterase by a regulatory PAS domain.

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