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

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, chem...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2018-06, Vol.140 (24), p.7471-7485
Main Authors: Bhate, Manasi P, Lemmin, Thomas, Kuenze, Georg, Mensa, Bruk, Ganguly, Soumya, Peters, Jason M, Schmidt, Nathan, Pelton, Jeffrey G, Gross, Carol A, Meiler, Jens, DeGrado, William F
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Bacitracin - pharmacology
Bacterial Proteins - chemistry
Bacterial Proteins - genetics
Gene Knockout Techniques
Histidine Kinase - chemistry
Histidine Kinase - genetics
Hydrophobic and Hydrophilic Interactions
Magnetic Resonance Spectroscopy
Membrane Proteins - chemistry
Membrane Proteins - genetics
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Nisin - pharmacology
Protein Conformation, alpha-Helical
Protein Domains
Staphylococcus aureus - drug effects
Staphylococcus aureus - enzymology
Staphylococcus aureus - genetics
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.7b09670