The Cation-π Box is a Specific Phosphatidylcholine Membrane Targeting Motif

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Apr 12

PMID 23576432

Citations 23

Authors

Jiongjia Cheng

Rebecca Goldstein

Anne Gershenson

Boguslaw Stec

Mary F Roberts

Affiliations

Soon will be listed here.

Abstract

Peripheral membrane proteins can be targeted to specific organelles or the plasma membrane by differential recognition of phospholipid headgroups. Although molecular determinants of specificity for several headgroups, including phosphatidylserine and phosphoinositides are well defined, specific recognition of the headgroup of the zwitterionic phosphatidylcholine (PC) is less well understood. In cytosolic proteins the cation-π box provides a suitable receptor for choline recognition and binding through the trimethylammonium moiety. In PC, this moiety might provide a sufficient handle to bind to peripheral proteins via a cation-π cage, where the π systems of two or more aromatic residues are within 4-5 Å of the quaternary amine. We prove this hypothesis by engineering the cation-π box into secreted phosphatidylinositol-specific phospholipase C from Staphylococcus aureus, which lacks specific PC recognition. The N254Y/H258Y variant selectively binds PC-enriched vesicles, and x-ray crystallography reveals N254Y/H258Y binds choline and dibutyroylphosphatidylcholine within the cation-π motif. Such simple PC recognition motifs could be engineered into a wide variety of secondary structures providing a generally applicable method for specific recognition of PC.

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References

Lemmon M . Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol. 2008; 9(2):99-111. DOI: 10.1038/nrm2328. View

Pittelkow M, Tschapek B, Smits S, Schmitt L, Bremer E . The crystal structure of the substrate-binding protein OpuBC from Bacillus subtilis in complex with choline. J Mol Biol. 2011; 411(1):53-67. DOI: 10.1016/j.jmb.2011.05.037. View

Pu M, Roberts M, Gershenson A . Fluorescence correlation spectroscopy of phosphatidylinositol-specific phospholipase C monitors the interplay of substrate and activator lipid binding. Biochemistry. 2009; 48(29):6835-45. PMC: 2753481. DOI: 10.1021/bi900633p. View

Zhou C, Qian X, Roberts M . Allosteric activation of phosphatidylinositol-specific phospholipase C: specific phospholipid binding anchors the enzyme to the interface. Biochemistry. 1997; 36(33):10089-97. DOI: 10.1021/bi970846o. View

Moser J, Gerstel B, Meyer J, Chakraborty T, Wehland J, Heinz D . Crystal structure of the phosphatidylinositol-specific phospholipase C from the human pathogen Listeria monocytogenes. J Mol Biol. 1997; 273(1):269-82. DOI: 10.1006/jmbi.1997.1290. View

Lovgren , Carlson , Eskils , Kolsto . Localization of putative virulence genes on a physical map of the bacillus thuringiensis subsp. gelechiae chromosome . Curr Microbiol. 1998; 37(4):245-50. DOI: 10.1007/s002849900373. View

Feng J, Wehbi H, Roberts M . Role of tryptophan residues in interfacial binding of phosphatidylinositol-specific phospholipase C. J Biol Chem. 2002; 277(22):19867-75. DOI: 10.1074/jbc.M200938200. View

Collins R, Northrop J, Horton J, Lee D, Zhang X, Stallcup M . The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat Struct Mol Biol. 2008; 15(3):245-50. PMC: 2586904. DOI: 10.1038/nsmb.1384. View

Cheng J, Karri S, Grauffel C, Wang F, Reuter N, Roberts M . Does changing the predicted dynamics of a phospholipase C alter activity and membrane binding?. Biophys J. 2013; 104(1):185-95. PMC: 3540254. DOI: 10.1016/j.bpj.2012.11.015. View

10.

Roderick S, Chan W, Agate D, Olsen L, Vetting M, Rajashankar K . Structure of human phosphatidylcholine transfer protein in complex with its ligand. Nat Struct Biol. 2002; 9(7):507-11. DOI: 10.1038/nsb812. View

11.

Shi X, Shao C, Zhang X, Zambonelli C, Redfield A, Head J . Modulation of Bacillus thuringiensis phosphatidylinositol-specific phospholipase C activity by mutations in the putative dimerization interface. J Biol Chem. 2009; 284(23):15607-18. PMC: 2708857. DOI: 10.1074/jbc.M901601200. View

12.

Krissinel E, Henrick K . Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2256-68. DOI: 10.1107/S0907444904026460. View

13.

. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr. 1994; 50(Pt 5):760-3. DOI: 10.1107/S0907444994003112. View

14.

Goldstein R, Cheng J, Stec B, Roberts M . Structure of the S. aureus PI-specific phospholipase C reveals modulation of active site access by a titratable π-cation latched loop. Biochemistry. 2012; 51(12):2579-87. PMC: 3332126. DOI: 10.1021/bi300057q. View

15.

Kutateladze T . Translation of the phosphoinositide code by PI effectors. Nat Chem Biol. 2010; 6(7):507-13. PMC: 3182472. DOI: 10.1038/nchembio.390. View

16.

van Meer G, Voelker D, Feigenson G . Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008; 9(2):112-24. PMC: 2642958. DOI: 10.1038/nrm2330. View

17.

Tripsianes K, Madl T, Machyna M, Fessas D, Englbrecht C, Fischer U . Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins. Nat Struct Mol Biol. 2011; 18(12):1414-20. DOI: 10.1038/nsmb.2185. 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.

Schiefner A, Breed J, Bosser L, Kneip S, Gade J, Holtmann G . Cation-pi interactions as determinants for binding of the compatible solutes glycine betaine and proline betaine by the periplasmic ligand-binding protein ProX from Escherichia coli. J Biol Chem. 2003; 279(7):5588-96. DOI: 10.1074/jbc.M309771200. View

20.

Concha N, Head J, Kaetzel M, Dedman J, Seaton B . Rat annexin V crystal structure: Ca(2+)-induced conformational changes. Science. 1993; 261(5126):1321-4. DOI: 10.1126/science.8362244. View