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Copper Starvation-Inducible Protein for Cytochrome Oxidase Biogenesis in Bradyrhizobium Japonicum

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Copper Starvation-Inducible Protein for Cytochrome Oxidase Biogenesis in Bradyrhizobium Japonicum Research Collection Doctoral Thesis Copper starvation-inducible protein for cytochrome oxidase biogenesis in Bradyrhizobium japonicum Author(s): Serventi, Fabio Publication Date: 2012 Permanent Link: https://doi.org/10.3929/ethz-a-007595567 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 20824 COPPER STARVATION-INDUCIBLE PROTEIN FOR CYTOCHROME OXIDASE BIOGENESIS IN BRADYRHIZOBIUM JAPONICUM A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by FABIO SERVENTI Master of Science in Molecular Biology, Università degli Studi di Parma, Italy Born on July 12th, 1983 citizen of Italy accepted on the recommendation of: Prof. Dr. Hauke Hennecke, examiner Prof. Dr. Kaspar Locher, co-examiner Prof. Dr. Linda Thöny-Meyer, co-examiner 2012 Table of contents Summary 1 Riassunto 3 1 Introduction 5 1.1 Copper acquisition and trafficking in bacteria 6 1.1.1 Background 6 1.1.2 Periplasmic copper uptake in Gram-negative bacteria 17 1.1.3 Proteins for copper insertion into cuproenzymes 23 1.1.4 Copper import and trafficking in the cytoplasm 34 1.1.5 Concluding remarks 41 1.2 Copper sorting in Bradyrhizobium japonicum 42 1.3 Aim of this work 47 2 Copper starvation‐inducible protein for cytochrome oxidase biogenesis in Bradyrhizobum japonicum 49 2.1 Summary 51 2.2 Introduction 52 2.3 Experimental procedures 54 2.3.1 Bacterial strains, media, and growth conditions 54 2.3.2 Mutant constructions 54 2.3.3 Complementation of ΔpcuABCDE 57 2.3.4 Determination of Cu atoms in copper-free BVM 57 2.3.5 RNA isolation and cDNA synthesis 58 2.3.6 Quantitative real-time polymerase chain reaction (qRT-PCR) 58 2.3.7 Primer extension 59 2.3.8 Microarrays 59 2.3.9 Plant growth 59 2.3.10 Bacteroid isolation 59 2.3.11 Nitrate and nitrite detection in the growth medium 60 2.3.12 Determination of cytochrome c oxidase activity in membrane fractions 60 2.3.13 Immunological techniques 60 2.3.14 Purification of PcuC and its derivatives 63 2.3.15 Test for Cu(I) binding to PcuC 64 2.3.16 Bioinformatic analyses 64 2.4 Results 65 2.4.1 Comparative transcription profile of cells grown at different copper concentrations 65 2.4.2 The pcuABCDE genes are transcribed as an operon 67 2.4.3 Predicted proteins encoded by the pcuABCDE operon suggest a role in copper trafficking 68 2.4.4 The ΔpcuABCDE strains have a pleiotropic phenotype 69 2.4.5 pcuC is the only essential gene of the pcuABCDE operon for all tested functions 72 2.4.6 B. japonicum possesses a second pcuC-like gene (blr7088) without an obvious function 73 2.4.7 PcuC is a Cu(I)-binding PCuAC-like protein 74 2.4.8 PcuC and ScoI are required for the symbiotically essential cbb3-type cytochrome oxidase 76 2.5 Discussion 77 3 In vivo effect of PcuC H79A and H113A/M115A substitutions 81 3.1 Summary 82 3.2 Introduction 82 3.3 Experimental procedures 83 3.3.1 Bacterial strains and media 83 3.3.2 Construction of the strains 83 3.3.3 Phenotypization of the strains 84 3.4 Results 85 3.4.1 H113 and M115 of PcuC are required in copper starvation 85 3.4.2 Nitrogenase activity of pcuC[H113A/M115A] is strongly impaired 85 3.4.3 The aa3 oxidase is defective in the pcuC[H113A/M115A] strain 86 3.5 Discussion 87 4 Future perspectives 89 4.1 A revised working model for cytochrome oxidase biogenesis 90 4.1.1 The newly emerging role of Sco in proteobacteria 90 4.1.2 PCuAC collaborates with Sco 91 4.2 Validating the model 92 4.3 Other possible copper trafficking proteins 93 References 95 Curriculum Vitae and Publications 117 Acknowledgments 119 Summary Copper is both a trace and a toxic element. The Cu2+/Cu+ couple potential is the highest among the biometals, making copper usage by life convenient for the extraction of electrons from molecules with already high redox potentials. For this chemical property copper enzymes are involved in electron transfer and redox reactions, for example in aerobic or anaerobic respiratory processes. For the same property, and because it is the most effective metal in binding biomolecules, copper is able to misplace other metal ions and/or catalyze the production of reactive oxygen species. In bacteria, this toxicity is a major menace both in the cytoplasm and in the periplasm. To deal with it bacteria compartmentalize copper enzymes outside the cytoplasm, where the most sensitive targets are located, use efficient efflux systems, and use metallochaperones to tightly control its transport to copper enzymes. In copper starvation conditions it is possible that import systems collaborate with metallochaperones in a more complex trafficking system. Such copper chaperones have been described mainly for the biogenesis of heme-copper oxidases in mitochondria and in their prokaryotic relatives belonging to the α-proteobacteria class like Rhodobacter and Bradyrhizobium japonicum. In the eukaryotic model, adopted also for prokaryotes, Sco1 transfers copper to (or reduces its cysteines of, or both) the CuA center of the cytochrome c oxidase, and Cox11 is responsible for the CuB center. Recently Sco has been linked to the biogenesis of CuB centers in prokaryotic aa3 and cbb3 oxidases (the latter containing only a CuB center) as well. Biogenesis of the cbb3 oxidase does not require Cox11- like proteins but instead is dependent on the integrity of predicted inner-membrane transporters. PCuAC protein has been identified as a collaborator of Sco for copper transfer to its same targets (CuA and CuB centers of aa3 oxidase and CuB center of cbb3 oxidase). The abundance of alternative terminal oxidases, most of them copper-dependent, is peculiar to the nitrogen fixing B. japonicum, and allows it to undergo different lifestyles such as free-living aerobiosis and anaerobiosis, and symbiosis (mainly with soybean). It has been shown that ScoI (Sco1-like) and CoxG (Cox11-like) collaborate for the biogenesis of the main aerobic aa3-type cytochrome c oxidase in B. japonicum, while for the symbiotically- essential cbb3 oxidase the situation is less clear, but genes belonging to the fixGHIS operon, among them a predicted P1B-type ATPase as product, are necessary. This work aimed at identifying genes involved in copper import and trafficking in B. japonicum. For this reason, a transcriptomic survey of genes up-regulated in copper starvation and a search for copper chaperone homologues were carried out. Both approaches converged in the identification of an operon, pcuABCDE. This operon is the only genomic region whose expression is higher in copper-free medium compared to copper excess. It 1 encodes putative polypeptides related to copper trafficking, among them the PCuAC homologue PcuC. Strains with a resistance cassette replacing the operon were constructed and different phenotypes were evaluated. Importantly, the mutants were found to be defective in copper- starved growth, in anaerobic growth and in symbiosis. To check whether the phenotype is due to impaired biogenesis of the terminal oxidases, quantitative measurements of the aa3 and cbb3 oxidase activites were carried out, revealing decreased functionality for both of them. Interestingly, the defect of the aa3 oxidase is restorable with copper supplementation. The cbb3 oxidase misfunction is evident only when the activity is tested on bacteroid membranes, while in free-living anaerobic cultures (where the cbb3 oxidase is also expressed) the defect is absent. The logical follow-up of the operon mutant characterization has been the creation of strains in which each single gene has been deleted, in order to assign to each ORF a weight in the different phenotypes observed for the whole operon mutant. Surprisingly, except for the anaerobic growth, for which seemingly all the genes have a partial role, the lack of pcuC was found to be the only determinant of the ΔpcuABCDE strain phenotype. Phenotypes of ΔscoI (previously characterized in this group) and ΔpcuC are strikingly similar. As for ΔpcuC, the cbb3 oxidase activity of ΔscoI is not impaired when membranes are isolated from anaerobically grown cells. The cbb3 oxidase activity of bacteroid membranes was then measured in the ΔscoI strain as well, as this has not been tried formerly, and importantly revealed a strong defect, as for that observed in ΔpcuC. Furthermore, in-vitro studies confirmed the hypothesized Cu+-binding nature of PcuC via conserved residues previously identified in the Thermus thermophilus homologue. ScoI and PcuC are copper-binding proteins collaborating for copper insertion into the cbb3 oxidase and into the aa3 oxidase. These results are compatible with what has been concurrently observed in Pseudomonas aeruginosa PA01, Rhodobacter sphaeroides and Rhodobacter capsulatus, enforcing both a new view of the role of Sco, which is no longer restricted to the copper transfer/reduction of CuA centers, and its close link to PCuAC. In this model it would be more likely that the soluble PCuAC binds copper as it enters the periplasm and transfers it to the inner membrane-anchored Sco, which then sorts it to membrane bound chaperones/copper-enzyme targets. In order to assess the validity of this model further in vitro copper transfer studies are needed. 2 Riassunto Il rame è sia un oligoelemento sia una sostanza tossica. Il potenziale della coppia Cu2+/Cu+ è il più alto tra i biometalli, rendendo il rame utile per l’estrazione di elettroni da molecole con un potenziale redox già elevato. Per questa caratteristica i cuproenzimi catalizzano principalmente trasferimenti di elettroni e reazioni redox, come ad esempio in svariati processi respiratori aerobici o anaerobici.
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