For the first time, the complex architecture of a protein that controls the transport of lipids between the two layers of a cell membrane has been described. With this structure, Biochemists from the University of Zurich have now gained insight into processes that trigger blood coagulation.
Membranes are thin walls that surround cells and protect their interior from the environment. These walls are composed of phospholipids, which, due to their amphiphilic nature, form bilayers with distinct chemical properties: While the outward-facing headgroups are charged, the core of the bilayer is hydrophobic, which prevents charged molecules from passing through.
The controlled flow of ions across the membrane, which is essential for the transmission of nerve impulses, is facilitated by ion channels, membrane proteins that provide gated pathways for ions. Analogous to ion channels, lipid scramblases facilitate the passage of phospholipids beween the two layers of a membrane, a process that plays a key role in the intitiation of blood coagulation. Until recently, however, the architecture of these lipid scramblases remained unknown
Now, for the first time, researchers from the Department of Biochemistry of the University of Zurich, have succeeded in the structure determination of a lipid scramblase. A team of scientists in the group of Professor Raimund Dutzler unveiled the structure of a lipid scramblase from the TMEM16 family by X-ray crystallography. The structure provides insight into the activation of the protein by calcium and the transport of lipids. The work has now been published in the scientific journal Nature.
The architecture of a new membrane protein family
Membrane proteins of the TMEM16 family show a unique functional breadth, since they include, besides ion channels, which are essential for regulating of smooth muscle contraction, olfaction and eptithelial chloride secretion, also proteins that act as lipid scramblases.
When activated by calcium, these lipid scramblases located in the plasma membrane of blood platelets trigger blood coagulation by facilitating the transport of the lipid phosphatidylserine to the surface of the cell. In order to understand this process, the researchers have characterized the structure and function of a closely related fungal TMEM16 lipid scramblase. Their work has revealed a novel protein architecture that is common to the entire family and offers insight into lipid transport.
“The protein contains a charged crevice, which traverses the membrane in the form of a spiral staircase. This allows the polar headgroup of lipids to move from one side of the membrane to the other,” explains first author Janine Brunner. In the vicinity of this crevice, there are bound calcium ions surrounded by conserved, negatively charged side chains. Mutations in the calcium binding site impair lipid transport. By studying the calcium dependence of channel activation in the related TMEM16 chloride channels by electrophysiology, the scientists demonstrated the conservation of this calcium binding mode within the TMEM16 family.
Basis for new therapies
The results form the basis for understanding previously unknown mechanisms of lipid transport. “We have now gained insight into the architecture and function of a family of proteins, the malfunctioning of which causes various hereditary diseases,” says the biochemist from UZH. The modulation of these proteins by specific drugs could be a potential strategy for novel therapies – such as the treatment of Scotts syndrome, a blood coagulation disorder, or of a muscle disease associated with the malfunctioning of TMEM16 proteins.
The project was funded by the European Research Council and the Swiss National Science Foundation’s National Center of Competence in Research “TransCure”.
Janine D. Brunner, Novandy. K. Lim, Stephan Schenck, Alessia Duerst and Raimund Dutzler. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature. November 12, 2014. doi: 10.1038/nature13984
Prof. Raimund Dutzler
Department of Biochemistry
University of Zurich
Tel.: +41 44 635 65 50
University of Zurich
Tel.: +41 44 634 44 39
Bettina Jakob | Universität Zürich
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences