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New insights into the tetrameric family of the Fur metalloregulators

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Abstract

The ferric uptake regulator (Fur) belongs to the family of the metal-responsive transcriptional regulators. Fur is a global regulator found in all proteobacteria. It controls the transcription of a wide variety of genes involved in iron metabolism but also in oxidative stress or virulence factor synthesis. As a general view, Fur proteins were considered to be dimeric proteins both in solution and when bound to DNA. However, our recent data demonstrate that Fur proteins can be classified into two subfamilies, according to their quaternary structure. The group of dimers is represented by E. coli, V. cholerae and Y. pestis Fur and the group of highly stable tetramers by P. aeruginosa and F. tularensis Fur. Here, another tetrameric structure of a PaFur mutant containing manganese and zinc metal ions is described. Through biochemical, structural and computational studies, we have deciphered the important structural characteristics of the tetramers and studied the main interactions responsible for their strength. Potential or mean force calculations for tetramer formation have been determinant to quantify these interactions. Moreover calculations allow us to propose that some conserved residues prevent the tetramerization in the subfamily of dimeric Fur.

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Acknowledgements

We acknowledge the use of resources of INEXT 2217 and the support of members of the HTX Lab (EMBL, Grenoble, France). We also thank the European Synchrotron Radiation Facility for access to beamlines FIP BM30A and ID30A-1. This work was fund by the CEA, the Laboratory of Excellence GRAL (ANR-11-LABX-49-01) and the LabEx ARCANE and CBH-EUR-GS (ANR-17-EURE-0003). S.N. was supported by the Region Rhône-Alpes (ARC santé).

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JP, SC and IM-S designed the research; SN, LA and JP carried out the biochemical and structural experiments, JP and PC resolved the structure; SN and SC did the theoretical work; JP, SN, SC and IM-S analyzed data; SN, JP, SC and IM-S wrote the paper.

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Correspondence to J. Pérard, S. Crouzy or I. Michaud-Soret.

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Nader, S., Pérard, J., Carpentier, P. et al. New insights into the tetrameric family of the Fur metalloregulators. Biometals 32, 501–519 (2019). https://doi.org/10.1007/s10534-019-00201-8

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