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Biosynthesis, remodeling and intracellular transport of GPI proteins and sphingolipids in yeast

English title Biosynthesis, remodeling and intracellular transport of GPI proteins and sphingolipids in yeast
Applicant Conzelmann Andreas
Number 131078
Funding scheme Project funding (Div. I-III)
Research institution Division de Biochimie Département de Biologie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Molecular Biology
Start/End 01.04.2010 - 31.08.2013
Approved amount 605'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Genetics

Keywords (8)

glycosylphosphatidylinositol; ceramide; Membranes; lipid biosynthesis; Glycosylphosphatidylinositol anchored proteins; lipid remodeling; sphingolipid; acyltransferases

Lay Summary (English)

Lead
Lay summary
Most lipids of eukaryotic cells form the basic lipid bilayer, which, together with membrane proteins, constitutes the cellular membranes. These membranes are impermeable to most molecules and allow the cells to protect their internal milieu from changes in the surrounding as well as to allocate their own contents to different membrane enclosed compartments (organelles). Beyond this barrier function, membranes are ordering platforms for complex molecular events. The lipids forming a membrane fall into countless structurally different classes and membranes from different cells or organelles contain very different lipid profiles. Cells alter their lipid profile during physiological responses to stresses and, in spite of the usually very high later diffusion rates, lipids also are not uniformly distributed in the plane of the membrane. This allows to accommodate and concentrate proteins into special membrane domains, thus enhancing their mutual interaction or activity. Our present research focuses on the structure and regulation of several lipid biosynthetic enzymes, the activity of which can be measured by appropriate biochemical assays. Some of the enzymes we are studying are exchanging lipid moieties of so called glycosylphosphatidylinositol (GPI) anchored membrane proteins while these proteins travel through the secretory pathway. This lipid exchange is necessary for the transport of these proteins to the cell surface. Most of our GPI studies are carried out in baker's yeast, which represents an excellent model system for human pathogens such as trypanosoma brucei, trypanosoma cruzi and aspergillus fumigatus as well as human cells. Other enzymes of interest are genes synthesizing glycerophospholipids and known and unknown proteins, which synthesize sphingolipids. All enzymes we study consist of integral membrane proteins and we are interested in determining the orientation of their catalytic centers with regard to the plane of the membrane. The orientation of these catalytic centers indicates whether substrates and products have to be transported through membranes. Our studies have to be classified as purely fundamental research and of no predictable benefit for human disease, ecology or economy. We however are convinced that the complete annotation of the yeast and human genomes and metaboloms, i.e. the complete listing of at least some basic functions for all gene products and of the gene(s) responsible for all measurable functions will open new perspectives and will allow to better understand and predict biological processes.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Adaptation of low-resolution methods for the study of yeast microsomal polytopic membrane proteins: a methodological review.
Bochud A Ramachandra N Conzelmann A. (2013), Adaptation of low-resolution methods for the study of yeast microsomal polytopic membrane proteins: a methodological review., in Biochem Soc Trans. , 41(1), 35-42.
Membrane topology of yeast alkaline ceramidase YPC1
Ramachandra N Conzelmann A. (2013), Membrane topology of yeast alkaline ceramidase YPC1, in Biochem J. , 452(3), 585-594.
A novel pathway of ceramide metabolism in Saccharomyces cerevisiae.
Voynova NS Vionnet C Ejsing CS Conzelmann A. (2012), A novel pathway of ceramide metabolism in Saccharomyces cerevisiae., in Biochem J. , 447(1), 103-114.
Role of mature sphingolipids in yeast: new tools.
Conzelmann A. (2012), Role of mature sphingolipids in yeast: new tools., in Mol Microbiol., 84(6), 991-994.
Topology of the microsomal glycerol-3-phosphate acyltransferase Gpt2p/Gat1p of Saccharomyces cerevisiae.
Pagac M Vazquez HM Bochud A Roubaty C Knöpfli C Vionnet C Conzelmann A. (2012), Topology of the microsomal glycerol-3-phosphate acyltransferase Gpt2p/Gat1p of Saccharomyces cerevisiae., in Mol Microbiol. , 86(5), 1156-1166.
Topology of 1-acyl-sn-glycerol-3-phosphate acyltransferases SLC1 and ALE1 and related membrane-bound O-acyltransferases (MBOATs) of Saccharomyces cerevisiae.
Pagac Martin, de la Mora Hector Vazquez, Duperrex Cécile, Roubaty Carole, Vionnet Christine, Conzelmann Andreas (2011), Topology of 1-acyl-sn-glycerol-3-phosphate acyltransferases SLC1 and ALE1 and related membrane-bound O-acyltransferases (MBOATs) of Saccharomyces cerevisiae., in The Journal of biological chemistry, 286(42), 36438-47.
Yeast cells lacking all known ceramide synthases continue to make complex sphingolipids and to incorporate ceramides into glycosylphosphatidylinositol (GPI) anchors.
Vionnet Christine, Roubaty Carole, Ejsing Christer S, Knudsen Jens, Conzelmann Andreas (2011), Yeast cells lacking all known ceramide synthases continue to make complex sphingolipids and to incorporate ceramides into glycosylphosphatidylinositol (GPI) anchors., in The Journal of biological chemistry, 286(8), 6769-79.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Regulation of Protein Trafficking and Function by Palmitoylation Talk given at a conference 23.08.2012 Oxford, UK, Ireland Conzelmann Andreas;
Lipids, Molecular & Cellular Biology of Poster 17.07.2011 Waterville Valley Resort, NH, USA, United States of America Conzelmann Andreas;
10th Yeast Lipid Conference Talk given at a conference 26.05.2011 Oulu, Finland, Finland Conzelmann Andreas; Vazquez De la Mora Hector; Voynova Natalia;


Self-organised

Title Date Place

Associated projects

Number Title Start Funding scheme
116802 Biosynthesis, remodeling and intracellular transport of GPI proteins and sphingolipids in yeast 01.04.2007 Project funding (Div. I-III)
146148 Topology and biological function of yeast lipid biosynthetic enzymes 01.09.2013 Project funding (Div. I-III)

Abstract

The research plan aims at a better understanding of the lipid remodeling in glycosylphosphatidylinositol (GPI) anchored proteins and its consequences for the transport and targeting of GPI proteins. We use in microsomal in vitro tests in order to understand the topology and the precise mechanisms used by the enzymes incorporating C26 fatty acids or ceramides into GPI anchors, to measure the specificity of these enzymes for their substrates and to understand how their substrates get access to the ER lumen, where lipid remodeling occurs. Since GPI proteins are partitioning into ceramide-enriched membrane domains for stability and transport, we also investigate the consequences of changes in ceramide biosynthesis for the targeting of GPI and other proteins.
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