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Exploring the Interplay of Lipids and Membrane Proteins

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Exploring the Interplay of Lipids and Membrane Proteins Exploring the Interplay of Lipids and Membrane Proteins Candan Ariöz Thesis cover: Theodosian land walls representing biological membranes. Copyright belongs to “Byzantium1200.com”. Used with permission. ©Candan Ariöz, Stockholm University 2014 ISBN 978-91-7447-882-2 pp 1-69 Printed in Sweden by Universitetservice AB, Stockholm 2014 Distributor: Department of Biochemistry and Biophysics, Stockholm University Aileme, (To my family) Every stormy night has a sunny morning. Never lose hope… Abstract The interplay between lipids and membrane proteins is known to affect membrane protein topology and thus have significant effect (control) on their functions. In this PhD thesis, the influence of lipids on the membrane protein function was studied using three different membrane protein models. A monotopic membrane protein, monoglucosyldiacylglyecerol synthase (MGS) from Acholeplasma laidlawii is known to induce intracellular vesi- cles when expressed in Escherichia coli. The mechanism leading to this un- usual phenomenon was investigated by various biochemical and biophysical techniques. The results indicated a doubling of lipid synthesis in the cell, which was triggered by the selective binding of MGS to anionic lipids. Mul- tivariate data analysis revealed a good correlation with MGS production. Furthermore, preferential anionic lipid sequestering by MGS was shown to induce a different fatty acid modeling of E. coli membranes. The roles of specific lipid binding and the probable mechanism leading to intracellular vesicle formation were also investigated. As a second model, a MGS homolog from Synechocystis sp. PCC6803 was selected. MgdA is an integral membrane protein with multiple transmem- brane helices and a unique membrane topology. The influence of different type of lipids on MgdA activity was tested with different membrane frac- tions of Synechocystis. Results indicated a very distinct profile compared to Acholeplasma laidlawii MGS. SQDG, an anionic lipid was found to be the species of the membrane that increased the MgdA activity 7-fold whereas two other lipids (PG and PE) had only minor effects on MgdA. Additionally, a working model of MgdA for the biosynthesis and flow of sugar lipids be- tween Synechocystis membranes was proposed. The last model system was another integral membrane protein with a distinct structure but also a different function. The envelope stress sensor, CpxA and its interaction with E. coli membranes were studied. CpxA autophosphoryla- tion activity was found to be positively regulated by phosphatidylethanola- mine and negatively by anionic lipids. In contrast, phosphorylation of CpxR by CpxA revealed to be increased with PG but inhibited by CL. Non-bilayer lipids had a negative impact on CpxA phosphotransfer activity. Taken together, these studies provide a better understanding of the signifi- cance of the interplay of lipids and model membrane proteins discussed here. List of Publications This thesis is based on the following papers, which will be referred to in the text by their Roman numerals: I. C Ariöz, W Ye, A Bakali, C Ge, J Liebau, H Götzke, A Barth, L Mäler, Å Wieslander. (2013) Anionic lipid binding to the foreign protein MGS provides a tight coupling between phospholipid synthesis and protein overexpression in Escherichia coli. Biochemistry. 52 (33): 5533-5544 II. C Ariöz, H Götzke, L Lindholm, J Eriksson, K Edwards, DO Daley, A Barth, Å Wieslander. (2014) Heterologous overexpression of a monotopic glucosyltransferase (MGS) induces fatty acid remodeling in Escherichia coli membranes. BBA-Biomembranes. In press III. TT Selão, L Zhang, C Ariöz, Å Wieslander, B Norling. (2014) Subcellular localization of monoglucosyldiacylglycerol synthase in Synechocystis sp. PCC6803 and its unique regulation by lipid environment. PLoS ONE. 9 (2): e88153 IV. R Keller*, F Stenberg-Bruzell*, M Burstedt*, C Ariöz, D Wikström, A Kelly, Å Wieslander, DO Daley, S Hunke. (2014) The Escherichia coli envelope stress sensor CpxA can sense changes in lipid bilayer properties. Manuscript * These authors contributed equally Reprints were made with permission from the publishers. Additional publications: V. L Lindholm, C Ariöz, M Jawurek, J Liebau, L Mäler, C von Balmoos, A Barth, Å Wieslander. (2014) Effect of lipid bilayer properties on the photocycle of green proteorhodopsin. Submitted VI. C Ariöz*, P Uzdavinys*, O Beckstein, Å Wieslander, D Drew. (2014) The regulation of NapA activity by membrane lipid properties. Manuscript * These authors contributed equally Contents 1. Introduction .............................................................................................. 13 2. Biological Membranes.............................................................................. 14 2.1. Membrane Lipids ...................................................................................................15 2.1.1. Escherichia coli .............................................................................................16 2.1.2. Acholeplasma laidlawii ..................................................................................18 2.1.3. Synechocystis sp. PCC6803.........................................................................18 2.2. Physicochemical Properties of Lipids ....................................................................19 2.2.1. Fatty acid modifications.................................................................................19 2.2.2. Headgroup diversity ......................................................................................21 2.2.3. Backbone diversity ........................................................................................21 2.2.4. Lipid/protein ratio...........................................................................................22 2.2.5. Bilayer-prone/Non-bilayer prone ratio ...........................................................22 2.3. Membrane Proteins ...............................................................................................24 2.3.1. Peripheral (membrane-associated) proteins .................................................24 2.3.2. Integral membrane proteins ..........................................................................25 3. Lipid-protein Interactions.......................................................................... 27 3.1. Types of Interactions .............................................................................................27 3.1.1. 1st shell lipids (Annular lipids)........................................................................27 3.1.2. 1st shell lipids (Interfacial Lipids) ...................................................................28 3.1.3. Non-annular Lipids ........................................................................................29 3.1.4. Bulk Lipids.....................................................................................................30 3.2. Membrane Curvature.............................................................................................30 3.2.1. Modulating membrane curvature by lipid asymmetry....................................32 3.2.2. Modulating membrane curvature by protein scaffolds ..................................33 3.3. Intracellular Vesicles..............................................................................................34 3.3.1. Vesiculation by MGS.....................................................................................34 3.3.2. Vesiculation by other membrane proteins.....................................................35 4. Methodology ............................................................................................ 37 4.1. Model Membrane Systems....................................................................................37 4.1.1. Micelles .........................................................................................................37 4.1.2. Bicelles..........................................................................................................38 4.1.3. Vesicles.........................................................................................................39 4.2. Approaches to Study Lipid-Protein Interactions ....................................................40 4.2.1. Lipid-Fishing Method.....................................................................................40 4.2.2. Phosphorous NMR (31P-NMR) ......................................................................41 4.2.3. Fourier Transform Infrared Spectroscopy .....................................................42 4.2.4. Cryo-transmission electron microscopy ........................................................44 4.2.5. GFP-based promoter activity assay ..............................................................44 5. Summary of Papers ................................................................................. 46 6. Concluding remarks and future perspectives........................................... 51 7. Populärvetenskaplig sammanfattning på svenska................................... 53 8. Türkçe Özet ............................................................................................. 53 9. Acknowledgements.................................................................................. 56 10. Dedication to Åke................................................................................... 60 References................................................................................................... 61 Abbreviations AD93 Escherichia
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