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Structure and supramolecular organization of membrane transport proteins

English title Structure and supramolecular organization of membrane transport proteins
Applicant Fotiadis Dimitrios
Number 162581
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Biophysics
Start/End 01.12.2015 - 31.05.2019
Approved amount 525'000.00
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All Disciplines (2)

Discipline
Biophysics
Biochemistry

Keywords (12)

membrane transport protein; glucose transport protein; crystallization; X-ray crystallography; membrane protein; electron crystallography; X-ray crystallography; structure; cation-chloride cotransporter; two-dimensional crystal; three-dimensional crystal; transmission electron microscopy

Lay Summary (German)

Lead
Membrantransporter sind Eiweisse, die sich in Zellmembranen befinden und für das Überleben von Zellen wichtig sind. Sie schleusen Nahrung in lebende Zellen ein und schleusen Abfallprodukte, die im Stoffwechsel entstanden sind, aus. Zudem gelangen zahlreiche Medikamente über solche Transporter in die Zellen. Ziel dieses Projektes ist, die molekularen Transportmechanismen von bestimmten Membrantransportern zu verstehen.
Lay summary

Die Funktionsmechanismen von Membrantransportern sind heute noch schlecht verstanden. Diese können mittels biochemischen und biophysikalischen Methoden studiert werden. Weiterhin kann die dreidimensionale Anordnung der Atome in Membrantransportern mittels kristallographischer Strukturaufklärung bestimmt werden. Strukturen von Membrantransportern und von Proteinen im allgemeinen sind enorm hilfreich für das Verständnis deren Funktionen. Strukturelle und funktionelle Erkenntnisse über Membrantransportern können sehr wertvoll für die Entwicklung von neuen Arzneistoffen sein. In diesem Projekt werden verschiedene Membrantransporter studiert, wie z.B. Zucker und Salztransporter.  

 

Direct link to Lay Summary Last update: 18.11.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Design and assembly of a chemically switchable and fluorescently traceable light-driven proton pump system for bionanotechnological applications
Hirschi S., Fischer N., Kalbermatter D., Laskowski P. R., Ucurum Z., Müller D. J., Fotiadis D. (2019), Design and assembly of a chemically switchable and fluorescently traceable light-driven proton pump system for bionanotechnological applications, in Scientific Reports, 9(1), 1046-1046.
Mechanistic basis of L-lactate transport in the SLC16 solute carrier family
Bosshart Patrick D., Kalbermatter David, Bonetti Sara, Fotiadis Dimitrios (2019), Mechanistic basis of L-lactate transport in the SLC16 solute carrier family, in Nature Communications, 10(1), 2649-2649.
Bacterial Cell Walls and Membranes
Bosshart Patrick D., Fotiadis Dimitrios (2019), Bacterial Cell Walls and Membranes, Springer International Publishing, Cham.
Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies
Thoma Johannes, Manioglu Selen, Kalbermatter David, Bosshart Patrick D., Fotiadis Dimitrios, Müller Daniel J. (2018), Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies, in Communications Biology, 1(1), 23-23.
Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes
Ritzmann Noah, Thoma Johannes, Hirschi Stephan, Kalbermatter David, Fotiadis Dimitrios, Müller Daniel J. (2017), Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes, in Biophysical Journal, 113(6), 1181-1186.
Electron crystallography reveals that substrate release from the PTS IIC glucose transporter is coupled to a subtle conformational change
Kalbermatter David, Chiu Po-Lin, Jeckelmann Jean-Marc, Ucurum Zöhre, Walz Thomas, Fotiadis Dimitrios (2017), Electron crystallography reveals that substrate release from the PTS IIC glucose transporter is coupled to a subtle conformational change, in Journal of Structural Biology, 199(1), 39-45.

Associated projects

Number Title Start Funding scheme
184980 Structures of solute carrier membrane transport proteins 01.07.2019 Project funding (Div. I-III)
125762 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase I) 01.11.2010 National Centres of Competence in Research (NCCRs)
144168 Structure and supramolecular organization of membrane transport proteins 01.11.2012 Project funding (Div. I-III)
184980 Structures of solute carrier membrane transport proteins 01.07.2019 Project funding (Div. I-III)

Abstract

Transport proteins are the gatekeepers of cells and cell organelles, and are involved in cellular nutrition, ionic homeostasis, disposal of waste products and uptake of certain drugs. Dysfunction of these membrane proteins leads to a number of serious human diseases. Yet the structural information required for understanding cellular transport and genetic disorders, and to design effective drugs is missing. High-resolution structures of pro- and eukaryotic transport proteins, and indeed of membrane proteins in general, are sparse compared to structures of water-soluble proteins. The reasons for this are mainly attributed to the amphiphilic nature of membrane proteins and the difficulty to overexpress them heterologously, e.g., for crystallization and structure determination by crystallographic approaches or solution nuclear magnetic resonance (NMR) analysis where milligram amounts of pure and homogenous proteins are indispensable.This Swiss National Science Foundation (SNSF) project proposal aims at elucidating structure, supramolecular organization and conformational states of the translocation cycle (e.g., inward- and outward-facing conformations) of selected prokaryotic and mammalian transport proteins by X-ray crystallography and cryo-transmission electron microscopy (cryo-TEM).Our target transport proteins are the glucose phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS) transporter from Escherichia coli IICGlc and the potassium-chloride cotransporter KCC4 from mouse. We address important open questions from the membrane transport protein field and aim to answer them by determining the medium- and high-resolution structures of our target proteins. These questions include the structural bases for the molecular working mechanisms of glucose PTS transporters and mammalian cation-chloride cotransporters. Knowledge of the structures of these transporters accompanied by functional studies such as structure-based site directed mutagenesis studies will improve our general understanding of transporter organization and architecture, and molecular transport mechanism.
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