Lysine Nzeta-decarboxylation Switch and Activation of the Beta-lactam Sensor Domain of BlaR1 Protein of Methicillin-resistant Staphylococcus Aureus

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Jul 22

PMID 21775440

Citations 16

Authors

Oleg Borbulevych

Malika Kumarasiri

Brian Wilson

Leticia I Llarrull

Mijoon Lee

Dusan Hesek

Qicun Shi

Jeffrey Peng

Brian M Baker

Shahriar Mobashery

Affiliations

Soon will be listed here.

Abstract

The integral membrane protein BlaR1 of methicillin-resistant Staphylococcus aureus senses the presence of β-lactam antibiotics in the milieu and transduces the information to the cytoplasm, where the biochemical events that unleash induction of antibiotic resistance mechanisms take place. We report herein by two-dimensional and three-dimensional NMR experiments of the sensor domain of BlaR1 in solution and by determination of an x-ray structure for the apo protein that Lys-392 of the antibiotic-binding site is posttranslationally modified by N(ζ)-carboxylation. Additional crystallographic and NMR data reveal that on acylation of Ser-389 by antibiotics, Lys-392 experiences N(ζ)-decarboxylation. This unique process, termed the lysine N(ζ)-decarboxylation switch, arrests the sensor domain in the activated ("on") state, necessary for signal transduction and all the subsequent biochemical processes. We present structural information on how this receptor activation process takes place, imparting longevity to the antibiotic-receptor complex that is needed for the induction of the antibiotic-resistant phenotype in methicillin-resistant S. aureus.

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References

Word J, Lovell S, Richardson J, Richardson D . Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J Mol Biol. 1999; 285(4):1735-47. DOI: 10.1006/jmbi.1998.2401. View

McRee D . XtalView/Xfit--A versatile program for manipulating atomic coordinates and electron density. J Struct Biol. 1999; 125(2-3):156-65. DOI: 10.1006/jsbi.1999.4094. View

Bou G, Santillana E, Sheri A, Beceiro A, Sampson J, Kalp M . Design, synthesis, and crystal structures of 6-alkylidene-2'-substituted penicillanic acid sulfones as potent inhibitors of Acinetobacter baumannii OXA-24 carbapenemase. J Am Chem Soc. 2010; 132(38):13320-31. PMC: 3393087. DOI: 10.1021/ja104092z. View

Kerff F, Charlier P, Colombo M, Sauvage E, Brans A, Frere J . Crystal structure of the sensor domain of the BlaR penicillin receptor from Bacillus licheniformis. Biochemistry. 2003; 42(44):12835-43. DOI: 10.1021/bi034976a. View

Golemi D, Maveyraud L, Vakulenko S, Samama J, Mobashery S . Critical involvement of a carbamylated lysine in catalytic function of class D beta-lactamases. Proc Natl Acad Sci U S A. 2001; 98(25):14280-5. PMC: 64673. DOI: 10.1073/pnas.241442898. View

Wilke M, Hills T, Zhang H, Chambers H, Strynadka N . Crystal structures of the Apo and penicillin-acylated forms of the BlaR1 beta-lactam sensor of Staphylococcus aureus. J Biol Chem. 2004; 279(45):47278-87. DOI: 10.1074/jbc.M407054200. View

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View

Pervushin K, Riek R, Wider G, Wuthrich K . Attenuated T2 relaxation by mutual cancellation of dipole-dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution. Proc Natl Acad Sci U S A. 1997; 94(23):12366-71. PMC: 24947. DOI: 10.1073/pnas.94.23.12366. View

Vriend G . WHAT IF: a molecular modeling and drug design program. J Mol Graph. 1990; 8(1):52-6, 29. DOI: 10.1016/0263-7855(90)80070-v. View

10.

Zhang H, Hackbarth C, Chansky K, Chambers H . A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science. 2001; 291(5510):1962-5. DOI: 10.1126/science.1055144. View

11.

Llarrull L, Testero S, Fisher J, Mobashery S . The future of the β-lactams. Curr Opin Microbiol. 2010; 13(5):551-7. PMC: 6878888. DOI: 10.1016/j.mib.2010.09.008. View

12.

Llarrull L, Fisher J, Mobashery S . Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new beta-lactams that meet the challenge. Antimicrob Agents Chemother. 2009; 53(10):4051-63. PMC: 2764218. DOI: 10.1128/AAC.00084-09. View

13.

Birck C, Cha J, Cross J, Schulze-Briese C, Meroueh S, Schlegel H . X-ray crystal structure of the acylated beta-lactam sensor domain of BlaR1 from Staphylococcus aureus and the mechanism of receptor activation for signal transduction. J Am Chem Soc. 2004; 126(43):13945-7. DOI: 10.1021/ja044742u. View

14.

Docquier J, Calderone V, De Luca F, Benvenuti M, Giuliani F, Bellucci L . Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. Chem Biol. 2009; 16(5):540-7. DOI: 10.1016/j.chembiol.2009.04.010. View

15.

Kay L, Torchia D, Bax A . Backbone dynamics of proteins as studied by 15N inverse detected heteronuclear NMR spectroscopy: application to staphylococcal nuclease. Biochemistry. 1989; 28(23):8972-9. DOI: 10.1021/bi00449a003. View

16.

Sun T, Nukaga M, Mayama K, Braswell E, Knox J . Comparison of beta-lactamases of classes A and D: 1.5-A crystallographic structure of the class D OXA-1 oxacillinase. Protein Sci. 2002; 12(1):82-91. PMC: 2312410. DOI: 10.1110/ps.0224303. View

17.

Docquier J, Benvenuti M, Calderone V, Giuliani F, Kapetis D, De Luca F . Crystal structure of the narrow-spectrum OXA-46 class D beta-lactamase: relationship between active-site lysine carbamylation and inhibition by polycarboxylates. Antimicrob Agents Chemother. 2010; 54(5):2167-74. PMC: 2863608. DOI: 10.1128/AAC.01517-09. View

18.

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

19.

Perrakis A, Sixma T, Wilson K, Lamzin V . wARP: improvement and extension of crystallographic phases by weighted averaging of multiple-refined dummy atomic models. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 4):448-55. DOI: 10.1107/S0907444997005696. View

20.

Golemi-Kotra D, Cha J, Meroueh S, Vakulenko S, Mobashery S . Resistance to beta-lactam antibiotics and its mediation by the sensor domain of the transmembrane BlaR signaling pathway in Staphylococcus aureus. J Biol Chem. 2003; 278(20):18419-25. DOI: 10.1074/jbc.M300611200. View