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
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy