YlaN is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in<i>Staphylococcus aureus</i>

Boyd, Jeffrey M.; Esquilín-Lebrón, Karla; Campbell, Courtney J.; Kaler, Kylie Ryan; Norambuena, Javiera; Foley, Mary E.; Stephens, Timothy G.; Rios, Gustavo; Mereddy, Gautam; Zheng, Vincent; Bovermann, Hannah; Kim, Jisun; Kulczyk, Arkadiusz W.; Yang, Jason H.; Greco, Todd M.; Cristea, Ileana M.; Carabetta, Valerie J.; Beavers, William N.; Bhattacharya, Debashish; Skaar, Eric P.; Parker, Dane; Carroll, Ronan K.; Stemmler, Timothy L.

doi:10.1101/2023.10.03.560778

Cited by 3 publications

(1 citation statement)

References 95 publications

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“…3b ). We show here that it requires the recruitment of the Fur DNA-binding domains by the iron(II)-sensitive Fpa 25 to secure the release of Fur from DNA and thereby iron homeostasis in low iron conditions ( Fig. 3e ).…”

Section: Alphalink Reveals the Long-enigmatic Molecular Basis Of Iron...mentioning

confidence: 70%

Modelling protein complexes with crosslinking mass spectrometry and deep learning

Stahl

Brock

Rappsilber

2023

Preprint

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Scarcity of structural and evolutionary information on protein complexes poses a challenge to deep learning-based structure modelling. We integrated experimental distance restraints obtained by crosslinking mass spectrometry (MS) into AlphaFold-Multimer, by extending AlphaLink to protein complexes. Integrating crosslinking MS data substantially improves modelling performance on challenging targets, by helping to identify interfaces, focusing sampling, and improving model selection. This extends to single crosslinks from whole-cell crosslinking MS, suggesting the possibility of whole-cell structural investigations driven by experimental data.

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Section: Alphalink Reveals the Long-enigmatic Molecular Basis Of Iron...mentioning

confidence: 70%

Modelling protein complexes with crosslinking mass spectrometry and deep learning

Stahl

Brock

Rappsilber

2023

Preprint

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Control of iron homeostasis by a regulatory protein-protein interaction inBacillus subtilis: The FurA (YlaN) acts as an antirepressor to the ferric uptake regulator Fur

Demann,

Bremenkamp,

Stahl

et al. 2023

Preprint

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Iron is essential for most organisms. However, two problems are associated with the use of iron for aerobically growing organisms: (i) its accumulation leads to the formation of toxic reactive oxygen species and (ii) it is present mainly as the highly insoluble ferric iron which makes the access to iron difficult. As a consequence, a tight regulation of iron homeostasis is required. This regulation is achieved in many bacteria by the ferric uptake repressor Fur. The way how the activity of Fur is controlled, has so far remained elusive. Here, we have identified the Fur antirepressor FurA (previously YlaN) in the model bacteriumBacillus subtilisand describe its function to release Fur from the DNA under conditions of iron limitation. The FurA protein physically interacts with Fur, and this interaction prevents Fur from binding to its target sites due to a complete re-orientation of the protein. Bothin vivoandin vitroexperiments using a reporter fusion and Fur-DNA binding assays, respectively, demonstrate that the Fur-FurA interaction prevents Fur from binding DNA and thus from repressing the genes required for iron uptake. Accordingly, the lack of FurA results in the inability of the cell to express the genes for iron uptake under iron-limiting conditions. This explains why thefurAgene was identified as being essential under standard growth conditions inB. subtilis. Phylogenetic analysis suggests that the control of Fur activity by the antirepressor FurA is confined to, but very widespread in bacteria of the class Bacilli.IMPORTANCEIron is essential for most bacteria since it is required for many redox reactions. Under aerobic conditions, iron is both essential and toxic due to radical formation. Thus, iron homeostasis must be faithfully controlled. The transcription factor Fur is responsible for this regulation in many bacteria; however, the control of Fur activity has remained open. Here we describe the FurA protein, a so far unknown protein which acts as an antirepressor to Fur inBacillus subtilis. This mechanism seems to be widespread inB. subtilisand several important pathogens and might be a promising target for drug development.

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Analysis of genetic requirements and nutrient availability forStaphylococcus aureusgrowth in cystic fibrosis sputum

Shull,

Wolter,

Kunkle

et al. 2024

Preprint

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Staphylococcus aureusis one of the most common pathogens isolated from the lungs of people with cystic fibrosis (CF), but little is known about its ability to colonize this niche. We performed a Tn-seq screen to identify genes necessary forS. aureusgrowth in media prepared fromex vivoCF sputum. We identified 19 genes that were required for growth in all sputum media tested and dozens more that were required for growth in at least one sputum medium. Depleted mutants of interest included insertions in many genes important for surviving metal starvation as well as the primary regulator of cysteine metabolismcymR. To investigate the mechanisms by which these genes contribute toS. aureusgrowth in sputum, we quantified low-molecular-weight thiols, nutrient transition metals, and the host metal-sequestration protein calprotectin in sputum from 11 individuals with CF. In all samples, the abundance of calprotectin exceeded nutrient metal concentration, explaining theS. aureusrequirement for metal-starvation genes. Further, all samples contain potentially toxic quantities of cysteine and sufficient glutathione to satisfy the organic sulfur requirements ofS. aureus. Deletion of the cysteine importer genestcyAandtcyPin the ΔcymRbackground restored growth to wild-type levels in CF sputum, suggesting that the mechanism by whichcymRis required for growth in sputum is to prevent uncontrolled import of cysteine or cystine from this environment. Overall, this work demonstrates that calprotectin and cysteine limitS. aureusgrowth in CF sputum.

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YlaN is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression inStaphylococcus aureus

Cited by 3 publications

References 95 publications

Modelling protein complexes with crosslinking mass spectrometry and deep learning

Modelling protein complexes with crosslinking mass spectrometry and deep learning

Control of iron homeostasis by a regulatory protein-protein interaction inBacillus subtilis: The FurA (YlaN) acts as an antirepressor to the ferric uptake regulator Fur

Analysis of genetic requirements and nutrient availability forStaphylococcus aureusgrowth in cystic fibrosis sputum

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