4.7 Article

Heme controls the structural rearrangement of its sensor protein mediating the hemolytic bacterial survival

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COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s42003-021-01987-5

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  1. Japan Society for the Promotion of Science KAKENHI [JP26220807, JP18H02396, JP18K05321, 19H05761]
  2. Fumi Yamamura Memorial Foundation for Female Natural Scientists from Chuo Mitsui Trust and Banking
  3. Hyogo Science and Technology Association
  4. RIKEN Pioneering Project Integrated Lipidology
  5. RIKEN Pioneering Project Fundamental Principles Underlying the Hierarchy of Matter
  6. Cooperative Research Program of the Institute for Molecular Science [238]
  7. Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) for AMED [JP18am0101094]
  8. Grants-in-Aid for Scientific Research [19H05761] Funding Source: KAKEN

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The study elucidated the structural basis of the transcription regulator PefR from Streptococcus agalactiae, a pathogen causing life-threatening neonatal infections. Structural comparison in different states (apo, DNA-bound, heme-bound, CO-heme-bound, and CN-heme-bound PefRs) revealed a unique heme coordination controlling structural rearrangement for the survival of the hemolytic bacteria causing neonatal infections.
Hemes (iron-porphyrins) are critical for biological processes in all organisms. Hemolytic bacteria survive by acquiring b-type heme from hemoglobin in red blood cells from their animal hosts. These bacteria avoid the cytotoxicity of excess heme during hemolysis by expressing heme-responsive sensor proteins that act as transcriptional factors to regulate the heme efflux system in response to the cellular heme concentration. Here, the underlying regulatory mechanisms were investigated using crystallographic, spectroscopic, and biochemical studies to understand the structural basis of the heme-responsive sensor protein PefR from Streptococcus agalactiae, a causative agent of neonatal life-threatening infections. Structural comparison of heme-free PefR, its complex with a target DNA, and heme-bound PefR revealed that unique heme coordination controls a >20 angstrom structural rearrangement of the DNA binding domains to dissociate PefR from the target DNA. We also found heme-bound PefR stably binds exogenous ligands, including carbon monoxide, a by-product of the heme degradation reaction. Nishinaga et al. present structural characterization of the transcription regulator PefR from S. agalactiae in different states (apo-, DNAbound, heme-bound, CO-heme-bound and CN-heme-bound-PefRs). Structural comparison revealed that unique heme coordination controls structural rearrangement for the survival of the neonatal infection-causing hemolytic bacteria.

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