title: Investigation of signal transduction routes within the sensor/transducer protein BlaR1 of Staphylococcus aureus.
abstract: The transmembrane antibiotic sensor/signal transducer protein BlaR1 is part of a cohort of proteins that confer β-lactam antibiotic resistance in methicillin-resistant Staphylococcus aureus (MRSA) [Fisher, J. F., Meroueh, S. O., and Mobashery, S. (2005) Chem. Rev. 105, 395-424; Llarrull, L. I., Fisher, J. F., and Mobashery, S. (2009) Antimicrob. Agents Chemother. 53, 4051-4063; Llarrull, L. I., Toth, M., Champion, M. M., and Mobashery, S. (2011) J. Biol. Chem. 286, 38148-38158]. Specifically, BlaR1 regulates the inducible expression of β-lactamases that hydrolytically destroy β-lactam antibiotics. The resistance phenotype starts with β-lactam antibiotic acylation of the BlaR1 extracellular domain (BlaRS). The acylation activates the cytoplasmic protease domain through an obscure signal transduction mechanism. Here, we compare protein dynamics of apo versus antibiotic-acylated BlaRS using nuclear magnetic resonance. Our analyses reveal inter-residue interactions that relay acylation-induced perturbations within the antibiotic-binding site to the transmembrane helix regions near the membrane surface. These are the first insights into the process of signal transduction by BlaR1.
authors: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors: Michael W
authors: MW
authors: Staude
authors: Thomas E
authors: TE
authors: Frederick
authors: Sivanandam V
authors: SV
authors: Natarajan
authors: Brian D
authors: BD
authors: Wilson
authors: Carol E
authors: CE
authors: Tanner
authors: Steven T
authors: ST
authors: Ruggiero
authors: Shahriar
authors: S
authors: Mobashery
authors: Jeffrey W
authors: JW
authors: Peng
mesh_terms: D000215:Acylation; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D018440:beta-Lactam Resistance
chemical_list: D001426:Bacterial Proteins; C569108:BlaR1 protein, Staphylococcus aureus; D008666:Metalloendopeptidases