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Regulation of Neutral Lipid Metabolism Through Phosphorylation of the Yeast Acyltransferase Gpt2

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Regulation of Neutral Lipid Metabolism Through Phosphorylation of the Yeast Acyltransferase Gpt2 University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2018-10-04 Regulation of neutral lipid metabolism through phosphorylation of the yeast acyltransferase Gpt2 Tavassoli, Marjan Tavassoli, M. (2018). Regulation of neutral lipid metabolism through phosphorylation of the yeast acyltransferase Gpt2 (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/33158 http://hdl.handle.net/1880/108818 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Regulation of neutral lipid metabolism through phosphorylation of the yeast acyltransferase Gpt2 by Marjan Tavassoli A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOLOGICAL SCIENCES CALGARY, ALBERTA SEPTEMBER, 2018 © Marjan Tavassoli 2018 Abstract Glycerol-3-phosphate acyltransferases (GPATs) catalyze the first step of glycerol-3-phosphate acylation at the sn-1 position producing lyso-phosphatidic acid. This is the committed and rate limiting step in de-novo synthesis of phosphatidic acid, the key intermediate in the glycerophospholipids and triacylglycerols (TAG) biosynthetic pathways. Two GPATs have been identified in S cerevisiae, Gpt2p and Sct1p. The role of phosphorylation in the serine-rich C- terminal tail of Gpt2p is unknown. In this work is shown that lack of phosphorylation on three conserved phosphorylation sites (S664, S668, S671) of Gpt2p alters protein stability, activity and neutral lipid metabolism. Specifically, a triple Gpt2p mutant (Gpt2-3A) where all these three residues were converted to alanine to mimic dephosphorylation induce a rise in the protein abundance, displayed more activity and resultedi in higher accumulation of DAG and TAG during exponential phase of growth. Lack of phosphorylation on Gpt2p delayed TAG lipolysis upon growth resumption from stationary phase which might be due to a futile TAG cycle that slows down mobilization of produced acyl-chains channeled for the formation of phospholipids. Unregulated Gpt2p probably remains constitutively active and displaces Sct1p in exponential phase. Notoriously, Sct1p is found associated with lipid droplets in cells carrying Gpt2-3A mutant. Considering Sct1p has never been identified in lipid droplets proteomes this consequence of having a constitutively de-phosphorylated Gpt2p might explain the alterations seen in neutral lipid metabolism of this mutant cells. i Preface Chapter 3 of this thesis has been published as: Smart, Heather C., Fred D. Mast, Maxwell F.J. Chilije, Marjan Tavassoli, Joel B. Dacks, and Vanina Zaremberg. 2014. “Phylogenetic Analysis of Glycerol 3-Phosphate Acyltransferases in Opisthokonts Reveals Unexpected Ancestral Complexity and Novel Modern Biosynthetic Components.” PLoS ONE 9 (10). https://doi.org/10.1371/journal.pone.0110684. ii Acknowledgements I would like to thank my supervisor, Dr. Vanina Zaremberg for giving me the opportunity to peruse my goals in her research lab and for showing me how to elaborate my ideas and go beyond the limits. She gave me freedom to explore my scientific interests. I am very grateful for the scientific training I received in her lab. I would like to thank my committee members, Dr. Gordon Chua and Dr. Elmar Prenner for their support and advices. I would also like to thank our research collaborator, Dr. Karin Athenstaedt in university of Graz. I would like to thank the former and present lab members, specially Maxwell Chilije, Suriakarthiga Ganesan, Brittney Shabits and Laura Sosa for all your support and good memories that we had during my research work. Talking and working with you makes lab work so much more enjoyable. I would also appreciate all undergrad student helping me during my project, specially Anabel Cardenas, Ricky Chang and Patrick Sipila. I would like to thank Dr. Jana Patton-Vogt, Dr. Shirin Bonni and Dr. Peter Tieleman for taking on the respective roles of external examiner and neutral chair of my defence exam. Special thanks to my fiancé, Frashid, my best friend, partner, and love of life. Without your support and encouragement, I would not be able to finish this journey successfully. I would like to thank my dear parents and brothers for their love and care. Excited to see what the future has in store for us. iii Table of contents Abstract ................................................................................................................................ i Preface .................................................................................................................................. ii Acknowledgement ............................................................................................................... iii Table of Contents ................................................................................................................ iv List of Abbreviations ........................................................................................................... ix List of Figures ...................................................................................................................... xiii List of Tables ....................................................................................................................... xviii Chapter 1 – Introduction ................................................................................................... 1 1.1 Introductory Remarks ............................................................................................... 1 1.2 Major Lipid Classes in Eukaryotes ........................................................................... 2 1.3 Saccharomyces cerevisiae as model organism ......................................................... 8 1.4 De novo Glycerolipid Synthesis in Yeast ....................................................................11 1.5 Glycerolipid catabolism, remodeling pathways .........................................................18 1.5.1 Phospholipid remodeling ................................................................................18 1.6 Glycerol-3-Phosphate Acyltransferases (GPAT) ...................................................... 20 1.6.1 Gpt2p and Sct1p Topology and Phosphorylation .......................................... 21 1.6.2 Gpt2p and Sct1p Substrate Specificity and Localization ................................25 1.7 PA and DAG as Signaling Molecules .........................................................................28 1.8 TAG biogenesis and formation of lipid droplet ..........................................................32 1.9 Glycerolipid homeostasis during growth stages .........................................................40 1.10 Signalling pathways that regulate lipid metabolism .................................................43 1.11 Hypothesis and Goals ...............................................................................................45 Chapter 2 – Materials and Methods ....................................................................................47 iv 2.1 Yeast Strains, Plasmids, Primers, Culture Conditions, and Transformations ...........47 2.1.2 Gene cloning ...................................................................................................53 2.1.3 Site-directed mutagenesis ...............................................................................54 2.1.4 Yeast crossing and tetrad dissection ...............................................................55 2.2 Cell lysate and microsomal fraction preparation, Protein Determination, SDS-PAGE, and Western Blot ..................................................................................................................56 2.2.1 Cell Lysate preparation ..................................................................................56 2.2.2 Microsomal Fractionation ..............................................................................56 2.2.3 Protein determination, SDS PAGE and Western blot .....................................57 2.2.4 Phosphatase treatment experiment .................................................................58 2.3 GPAT activity assay ....................................................................................................58 2.4 Quantitative Real-Time PCR ......................................................................................59 2.4.1 Total RNA isolation .........................................................................................59 2.4.2 Revers transcription ........................................................................................60 2.4.3 Quantitative Real-time PCR ...........................................................................61 2.5 Plating (growing) on different carbon source conditions ...........................................62 2.5.1 Oleic acid experiment .....................................................................................62 2.5.2 Plating on fermentable and non-fermentable carbon sources .......................62 2.5.3 Gradual and acute glucose depletion experiment
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