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Structure and Function of the Transmembrane Domain of NsaS, an Antibiotic Sensing Histidine Kinase in Staphylococcus aureus.

Bhate MP, Lemmin T, Kuenze G, Mensa B, Ganguly S, Peters JM, Schmidt N, Pelton JG, Gross CA, Meiler J, DeGrado WF
J Am Chem Soc. 2018 140 (24): 7471-7485

PMID: 29771498 · PMCID: PMC6499544 · DOI:10.1021/jacs.7b09670

NsaS is one of four intramembrane histidine kinases (HKs) in Staphylococcus aureus that mediate the pathogen's response to membrane active antimicrobials and human innate immunity. We describe the first integrative structural study of NsaS using a combination of solution state NMR spectroscopy, chemical-cross-linking, molecular modeling and dynamics. Three key structural features emerge: First, NsaS has a short N-terminal amphiphilic helix that anchors its transmembrane (TM) bundle into the inner leaflet of the membrane such that it might sense neighboring proteins or membrane deformations. Second, the transmembrane domain of NsaS is a 4-helix bundle with significant dynamics and structural deformations at the membrane interface. Third, the intracellular linker connecting the TM domain to the cytoplasmic catalytic domains of NsaS is a marginally stable helical dimer, with one state likely to be a coiled-coil. Data from chemical shifts, heteronuclear NOE, H/D exchange measurements and molecular modeling suggest that this linker might adopt different conformations during antibiotic induced signaling.

MeSH Terms (14)

Anti-Bacterial Agents Bacitracin Bacterial Proteins Gene Knockout Techniques Histidine Kinase Hydrophobic and Hydrophilic Interactions Magnetic Resonance Spectroscopy Membrane Proteins Microbial Sensitivity Tests Molecular Dynamics Simulation Nisin Protein Conformation, alpha-Helical Protein Domains Staphylococcus aureus

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