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Membrane-Binding Mechanisms of Bacterial Phospholipid N-Methyltransferases = Membranbindemechanismen Bakterieller Phospholipid N

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Membrane-Binding Mechanisms of Bacterial Phospholipid N-Methyltransferases = Membranbindemechanismen Bakterieller Phospholipid N Membrane-binding mechanisms of bacterial phospholipid N -methyltransferases Dissertation to obtain the degree Doctor Rerum Naturalium (Dr. rer. nat.) at the Faculty of Biology and Biotechnology International Graduate School of Biosciences Ruhr-University Bochum Chair for Microbial Biology submitted by Linna Maria Danne from Hamburg Bochum, October 2015 First Supervisor: Prof. Dr. Franz Narberhaus Second Supervisor: Prof. Dr. Ralf Erdmann Membranbindemechanismen bakterieller Phospholipid N -Methyltransferasen Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) der Fakult¨at fur¨ Biologie und Biotechnologie an der internationalen Graduiertenschule Biowissenschaften der Ruhr-Universit¨at Bochum angefertigt am Lehrstuhl fur¨ Biologie der Mikroorganismen von Linna Maria Danne aus Hamburg Bochum, Oktober 2015 Referent: Prof. Dr. Franz Narberhaus Korreferent: Prof. Dr. Ralf Erdmann Danksagung Ein ganz besonderer Dank gilt meinem Doktorvater Prof. Dr. Franz Narberhaus fur¨ die M¨oglich- keit, meine Doktorarbeit an seinem Lehrstuhl anfertigen zu durfen¨ und fur¨ die Vergabe dieses interessanten Projekts. Herzlichen Dank fur¨ die Begleitung meiner Arbeit mit vielen wegwei- senden Ideen und Diskussionen, sowie fur¨ das stetige Interesse und Vertrauen in meine Arbeit. Zudem ein großes Dankesch¨on fur¨ die Erm¨oglichung von einigen Kooperationen, die sehr zum Gelingen dieser Arbeit beigetragen haben, sowie die M¨oglichkeit an internationalen Konferen- zen teilnehmen zu k¨onnen. Herrn Prof. Dr. Ralf Erdmann danke ich sehr herzlich fur¨ die freundliche Ubernahme¨ des Korreferats und die gute Zusammenarbeit bezuglich¨ der elektronenmikroskopischen Aufnah- men von Liposomen, die ebenfalls sehr zum guten Gelingen dieser Arbeit beigetragen hat. Bedanken m¨ochte ich mich bei allen anderen Kooperationspartnern, die einen wichtigen Bei- trag zu dieser Arbeit geleistet haben. Herrn Prof. Dr. Harald Schwalbe und Dominic Wagner (Goethe-Universit¨at Frankfurt) danke ich sehr herzlich fur¨ die Erm¨oglichung von Thermo- phorese-Messungen. Herrn Prof. Dr. Nils Metzler-Nolte und Barbara Hofknecht (Ruhr-Univer- sit¨at Bochum) danke ich fur¨ die chemische Herstellung von Peptiden. Ebenfalls danke an Dr. Claudia Lindemann (Ruhr-Universit¨at Bochum) fur¨ die Kooperation bezuglich¨ der Cross- Linking Experimente. Ein herzlicher Dank geht an Monika Burger¨ und Beate Menzel (Ruhr- Universit¨at Bochum) fur¨ die engagierte Unterstutzung¨ und tolle Zusammenarbeit bei der Er- stellung von elektronenmikroskopischen Aufnahmen von Liposomen. Herrn Dr. Bernd Masepohl, Frau Prof. Dr. Julia Bandow und Frau Prof. Dr. Nicole Frankenberg- Dinkel danke ich fur¨ hilfreiche Tipps und ideenreiche Diskussionen. Ein ganz besonderer Dank gilt Dr. Meriyem Aktas, die maßgeblich zum Gelingen dieser Arbeit beigetragen hat. Ich danke dir fur¨ deine Unterstutzung,¨ fur¨ viele Ideen und Diskussionen, fur¨ das Vertrauen, das du in meine Arbeit gesetzt hast und fur¨ all die vielen Dinge, die ich von dir gelernt habe. Dankesch¨on! Ganz herzlich danke ich allen derzeitigen und ehemaligen Mitgliedern der Arbeitsgruppe Mem- " branbiogenese\ fur¨ die sch¨one Zeit im Labor und Buro,¨ insbesondere Simon Czolkoss fur¨ viele Hilfestellungen und Ratschl¨age. Zudem ein herzlicher Dank an Dr. Jan Gleichenhagen fur¨ die Unterstutzung¨ in der Anfangszeit meiner Arbeit, Herrn Dr. Roman Moser fur¨ viele Ideen und Hilfestellungen im Labor, sowie Dr. Philip M¨oller fur¨ seine Unterstutzung¨ in vielen technischen Fragen. Christiane Fritz danke ich sehr fur¨ ihre Hilfe im Labor. Ein herzlicher Dank an meine\ " Studenten Nadine Grund, Tim Bentler und Melina Terhufen, danke fur¨ die sch¨one Zusammen- arbeit und fur¨ den Anteil den ihr zu dieser Arbeit beigetragen habt. Ein herzlicher Dank gilt Lisa-Marie Bittner fur¨ die riesen Unterstutzung¨ beim Korrekturle- sen dieser Arbeit, sowie fur¨ die sch¨one Zeit, die wir zusammen im Studium verbracht haben und fur¨ deine Unterstutzung¨ w¨ahrend des gesamten Studiums. Danke, dass ich mich immer auf dich verlassen kann. Ebenso danke ich Marie Hoffmann und Johanna Roßmanith fur¨ viele Hilfestellungen, ihre Unterstutzung¨ und die sch¨one gemeinsame Zeit im Studium. Herrn Hanno Boeddinghaus danke ich sehr herzlich fur¨ die Unterstutzung¨ bei vielen technischen Fragen und Frau Petra Kr¨amer fur¨ die Hilfe bei allen verwaltungstechnischen Angelegenheiten. Dem gesamten Lehrstuhl fur¨ Biologie der Mikroorganismen danke ich fur¨ das gute Arbeitskli- ma und die angenehme Zusammenarbeit. Der Research School Plus der Ruhr-Universit¨at Bochum danke ich fur¨ die finanzielle Un- terstutzung¨ fur¨ die Teilnahme an einer internationalen Konferenz. Nicht zuletzt danke ich meinen Freunden und ganz besonders meiner Familie. Von Herzen ein großes Dankesch¨on fur¨ eure Unterstutzung¨ und euer Verst¨andnis, in nicht immer reibungs- losen Zeiten. Ihr habt einen wesentlichen Teil zum Gelingen dieser Arbeit beigetragen. Meiner Mutter danke ich fur¨ ihre fortw¨ahrende Unterstutzung¨ und fur¨ den Freiraum den sie mir immer gew¨ahrt hat. Herzlichen Dank! In Gedenken an meine Großeltern Franz und Luise Danne geht ein besonderer Dank an euch. Durch eure Unterstutzung,¨ sowie den Mut, den ihr mir immer gegeben habt, habt ihr maß- geblich zum Gelingen dieser Arbeit beigetragen. Ohne euch w¨are ich nicht das was ich heute bin. Danke f¨ur Alles.\ " Table of contents Abbreviations ......................................... I-II A Introduction ........................................ 1 1 Structure and composition of bacterial membranes .................. 1 1.1 Membrane organization in bacteria ....................... 2 2 Membrane lipids - diversity and functions ....................... 3 2.1 Diversity in lipid architecture .......................... 4 2.2 Phospholipid-dependent membrane characteristics ............... 6 3 Protein-lipid interactions ................................ 7 4 Physiological role and biosynthesis of phosphatidylcholine in bacteria ......... 8 4.1 Phosphatidylcholine synthase pathway ..................... 10 4.2 Glycerophosphocholine (GPC)-dependent acylation pathway ......... 10 4.3 Methylation pathway .............................. 10 4.3.1 Methylation pathway in A. tumefaciens - catalyzed by a single PmtA enzyme 14 4.3.2 Structural properties of bacterial Pmts .................... 15 5 Objectives of this work ................................. 18 B Membrane-binding mechanism of a bacterial phospholipid N-methyltransferase . 19 C Principles governing membrane remodeling by a bacterial phospholipid methyl- ating enzyme ....................................... 52 D Comparative analysis of membrane-binding regions in three distinct bacterial phospholipid N-methyltransferases . 97 E Discussion ......................................... 138 1 Membrane-binding mechanism of bacterial phospholipid N-methyltransferases (Pmts) 138 1.2 Membrane-attachment sites of bacterial phospholipid N-methyltransferases (Pmts) .................................... 141 1.3 Membrane to cytosol cycling of bacterial phospholipid N-methyltransferases (Pmts) .................................... 146 1.4 αA - a conserved membrane-attachment site of bacterial Pmts? ....... 148 2 Membrane deformation - A common feature of bacterial Pmts? ........... 152 2.1 Dual membrane-remodeling mechanism of A. tumefaciens PmtA . 153 3 PmtA action is controlled by the membrane-lipid composition ............ 157 F Summary .......................................... 160 G Zusammenfassung .................................... 162 H References ......................................... 164 I Publications ........................................ 177 J Appendix .......................................... 178 Lebenslauf ......................................... 178 Eigenanteil an Publikationen ............................... 180 Erkl¨arung ......................................... 181 ___________________________________________________________________________Abbreviations Abbreviations Units of the International System of Units (SI) are not listed separately. The single letter code is used for designation of amino acids and nucleic acids. aa....................... Amino acid(s) AαA ................... N-terminal αA helix of A. tumefaciens PmtA AαF ....................Central αF helix of A. tumefaciens PmtA APmtA ............... A. tumefaciens PmtA BAαA ................. N-terminal αA helix of B. japonicum PmtA BAαF..................Central αF helix of B. japonicum PmtA BPmtA ............... B. japonicum PmtA bp ...................... Base pair CCT ....................Cytidine triphosphate phosphocholine cytidylyltransferase CDP .................... Cytidine diphosphate C-terminus ........ Carboxyl-terminus CL....................... Cardiolipin DAG ................... Diacylglycrol dNTP.................. 2‘-desoxynucleoside-5‘-triphosphate DMPE ................ Dimethyl-phosphatidylethanolamine Fig. ..................... Figure IPTG ..................Isopropyl β-D-thiogalactopyranoside kDa .................... Kilodalton Km ..................... Kanamycin LB....................... Luria Bertani broth MMPE ............... Monomethyl-phosphatidylethanolamine I ___________________________________________________________________________Abbreviations MTase ............... Methyltransferase NMR .................. Nuclear Magnetic Resonance N-terminus ....... Amino-terminus PA ...................... Phosphatidic acid PC ...................... Phosphatidylcholine Pcs ..................... Phosphatidylcholine
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