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Structural molecular biology of membrane proteins in signal transduction and cholesterol recognition

English title Structural molecular biology of membrane proteins in signal transduction and cholesterol recognition
Applicant Korkhov Volodymyr
Number 150665
Funding scheme SNSF Professorships
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Biochemistry
Start/End 01.04.2014 - 31.03.2018
Approved amount 1'599'760.00
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All Disciplines (2)

Discipline
Biochemistry
Biophysics

Keywords (6)

signal transduction; cholesterol; membrane protein; X-ray crystallography; cryo-electron microscopy; electron paramagnetic resonance

Lay Summary (German)

Lead
Alle lebenden Organismen sind auf eine effiziente inter- und intrazelluläre Interaktion angewiesen. Die Zellmembran ist der Ort, wo Kommunikation sowohl zwischen den Zellen als auch zwischen den membrangebundenen Zellkomponenten stattfindet. Schwerpunkt dieses Forschungsprojekts sind Membranproteine, die an der Zellkommunikation und an der Cholesterinerkennung beteiligt sind.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Das Ziel der ersten Forschungsrichtung ist die Identifizierung der präzisen Funktionsweise von einigen Proteinen der Zellmembran, die in der Signaltransduktion involviert sind – ein Prozess, bei welchem Signale (z.B. Hormone) von ausserhalb der Zelle in biochemische Reaktionen innerhalb der Zelle umgewandelt werden. Die Signalübertragung ist von enormer Bedeutung: viele Medikamente beeinflussen die Funktionsweise von Membranproteinen, die an der Signaltransduktion beteiligt sind. Das Ziel der zweiten Forschungsrichtung ist die detaillierte Beschreibung der Interaktion von Membranproteinen mit Cholesterin. Störungen in der Cholesterin-Homöostase, z.B. durch Mutationen in Proteinen, die mit Cholesterin interagieren, ist die Ursache für einige Krankheiten. Trotz der grossen Bedeutung der beiden Forschungsrichtungen, ist über die molekularen Einzelheiten dieser Prozesse nur wenig bekannt.

Der wissenschaftliche Ansatz beinhaltet eine Kombination von biochemischen, biophysikalischen und strukturbiologischen Techniken zur Bestimmung der Struktur und molekularen Funktionsweise der Membranproteine, welche in der Signaltransduktion und Cholesterinerkennung beteiligt sind.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Die Wichtigkeit der Erforschung von Membranproteinen wird durch die Anerkennung, die dieses Forschungsgebiet kürzlich erhalten hat, deutlich (Vergabe von Nobelpreisen in den letzten Jahren). Die Resultate dieser Grundlagenforschung werden nicht nur Erkenntnisse im Hinblick auf die Struktur und Funktionsweise der untersuchten Proteine liefern, sondern eröffnen potentiell neue Vorgehensweise in der biomedizinischen Forschung und führen eventuell zur Entwicklung von neuen Behandlungsmethoden von Krankheiten.

 

Direct link to Lay Summary Last update: 27.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Cryo-EM structure of the Hedgehog release protein Dispatched
Cannac Fabien, Qi Chao, Falschlunger Julia, Hausmann George, Basler Konrad, Korkhov Volodymyr M. (2020), Cryo-EM structure of the Hedgehog release protein Dispatched, in Science Advances, 6(16), eaay7928-eaay7928.
Expression, Purification, and Structural Biology of Membrane Proteins
Graeber Elisabeth, Korkhov Volodymyr M. (2020), Expression, Purification, and Structural Biology of Membrane Proteins, Springer US, New York, NY.
Characterisation of the ligand binding sites in the translocator protein TSPO using the chimeric bacterial-mammalian constructs
Graeber Elisabeth, Korkhov Volodymyr M. (2019), Characterisation of the ligand binding sites in the translocator protein TSPO using the chimeric bacterial-mammalian constructs, in Protein Expression and Purification, 164, 105456-105456.
Structural basis of sterol recognition by human hedgehog receptor PTCH1
Qi Chao, Di Minin Giulio, Vercellino Irene, Wutz Anton, Korkhov Volodymyr M. (2019), Structural basis of sterol recognition by human hedgehog receptor PTCH1, in Science Advances, 5(9), eaaw6490-eaaw6490.
The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein
Qi Chao, Sorrentino Simona, Medalia Ohad, Korkhov Volodymyr M. (2019), The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein, in Science, 364(6438), 389-394.
Expression and purification of the mammalian translocator protein for structural studies
Graeber Elisabeth, Korkhov Volodymyr M. (2018), Expression and purification of the mammalian translocator protein for structural studies, in PLOS ONE, 13(6), e0198832-e0198832.
Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation
Vercellino Irene, Rezabkova Lenka, Olieric Vincent, Polyhach Yevhen, Weinert Tobias, Kammerer Richard A., Jeschke Gunnar, Korkhov Volodymyr M. (2017), Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation, in Proceedings of the National Academy of Sciences, 114(46), E9821-E9828.

Collaboration

Group / person Country
Types of collaboration
Prof. Eilika Weber-Ban, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Gunnar Jeschke, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Dmitry Veprintsev, Paul Scherrer Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ohad Medalia, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Paola Picotti, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
5th International Meeting on Anchored cAMP Signaling Pathways Poster Structural basis of helical domain-assisted nucleotidyl cyclase dimerization 06.10.2016 Zermatt, Switzerland Korkhov Volodymyr;


Associated projects

Number Title Start Funding scheme
176992 Structural molecular biology of membrane proteins in signal transduction and cholesterol recognition 01.04.2018 SNSF Professorships
164092 Upgrade of a Titan Krios electron cryo-microscope for single particle analysis and tomography 01.12.2015 R'EQUIP
170808 Acquisition of a Talos Arctica transmission electron microscope for single particle analysis and cryo-tomography 01.05.2017 R'EQUIP
170802 Direct electron detector for cryo-EM single particle analysis, electron tomography and protein nanocrystallography 01.11.2017 R'EQUIP

Abstract

Membrane proteins are at the core of multiple cellular processes. This research project is aimed at elucidation of two important functions of membrane proteins: (i) signal transduction, and (ii) cholesterol recognition. Among the key tasks performed by membrane proteins is signal transduction, whereby extracellular signals received by the cell surface receptors are conveyed across the membrane to effector proteins. The effectors, some of which are integral membrane proteins, play a crucial role in cellular signalling. They convert the sensory input from outside the cell into a biochemical response inside the cell, leading to profound changes in cellular physiology. However, despite the importance of membrane-integral effector proteins in physiology, little is known about their structure, mechanism and modes of regulation by other signaling molecules. In addition to signal transduction, various membrane proteins are also involved in the recognition and translocation of a number of substrates, including ions, small molecule solutes and lipids, across the biological membranes. One such substrate is cholesterol, an essential component of many eukaryotic cell membranes. Many biological functions of cholesterol are determined by its interactions with membrane proteins, yet the current understanding of the molecular details of such interactions is insufficient. Using a combination of biochemical, biophysical and structural analysis, including EPR, cryo-EM and X-ray crystallography, I shall work towards unraveling the molecular details of structure and molecular mechanisms of membrane proteins involved in signal transduction and cholesterol recognition. The results will provide insights into these exciting branches of molecular biology, and will be of broad significance for biomedical research.
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