SCIENTISTS GAIN UNIQUE INSIGHT INTO THE FUNCTION OF A KEY MUSCLE PROTEIN
Thanks to the first high-resolution structural analysis of the muscle protein α-actinin, scientists now have a better understanding of how muscles work.
The analysis provides crucial information about the structure and function of this complex muscle protein and could lead to the development of new treatments for major muscular disorders.
The results of the project, which is funded by the Austrian Science Fund FWF and the European Commission, were recently published in the prestigious scientific journal Cell.
Muscles move many things – but first and foremost themselves. Filaments of special proteins pull against each other so that the muscle can exert force. This only works if there is a fixed point, which anchors the filaments.
These locations are known as Z-disks and are largely composed of the protein α-actinin. An international research team headed by Kristina Djinovic-Carugo from the Max F. Perutz Laboratories of the University of Vienna and Medical University of Vienna has taken a closer look at this protein.
FUNCTION FOLLOWS FORM
"We not only succeeded in describing the exact structure of the protein for the first time", explains Djinovic-Carugo, "we were also able to confirm the long-held assumption about how its function is regulated."
It emerged from the structural research that showed that α-actinin exists as a dimer, a complex consisting of two identical molecules, and that it displays a cylindrical shape, 360 Å in length (1 Å = 10 to the power of -10 metres) and 60 Å wide. Each individual molecule of the dimer has a head-and a neck-like structure followed by a four-part rod-shaped extension.
Two protein domains protruding from the rod-shaped extension in an L-shaped formation proved to be particularly interesting. "These L-shaped domains connect to the neck of the other molecule and this interaction is important for function", describes Djinovic-Carugo. "However, the really exciting discovery about these domains arose when we added the fatty acid molecule PIP2."
Scientists had actually speculated for years that PIP2 plays a key role in the functioning of muscle α-actinin. This hypothesis remained unconfirmed, however, until the following observation was made during the study of Djinovic-Carugo and her international colleagues in Germany, United Kingdom, Norway, Russia, Switzerland and Slovenia: as long as there is no PIP2 available, the L-shaped domain remains connected to the neck of the second α-actinin.
If PIP2 is available, the connection opens and renders the domain available to bind to another muscle protein – titin. The trick here – as revealed by the structural data from this FWF project – is that the neck region of the α-actinin is similar in structure to titin.
If there is no PIP2, one of the L-shaped domain of an α-actinin molecule binds to a titin-lookalike region in the neck of the opposing molecule. If PIP2 is present, the L-shaped part detaches from the neck and binds titin. The presence of PIP2 is sufficient to change the binding parameters in such a way that the one is prioritised over the other.
X-RAY VIEW OF THE CRYSTAL BALL
Regarding the methodology used in the study, Djinovic-Carugo says: "To deduce the functioning of a protein from its structure, you have to be able to identify everything down to a billionth of a metre. This is only really possible using X-ray diffraction, in which X-ray beams diffract when they encounter the fine structures of a protein, which is presented in the form of a crystal."
However, the decision to use this technology involved a tough test of the scientists’ patience at the outset: it took years to produce sufficient amounts of α-actinin to grow the protein crystals. The clarification of how α-actinin is regulated by PIP2 necessitated the use of other complicated complementary analysis methods, and this is where the expertise of Djinovic-Carugo’s international colleagues was indispensable. The comprehensive findings, which were recently acknowledged through the publication of the study in Cell, show that the long and concerted effort was worthwhile.
The importance of the project’s results extends far beyond the basic insights they provide. α-Actinin plays a role in the causes of life-threatening muscular disorders like dystrophies and cardiomyopathies. The new insights into the structure and function of this protein could lead to the development of new approaches to their treatment.
Professor Kristina Djinovic-Carugo is an internationally renowned expert in the x-ray diffraction of proteins. She heads the Department of Structural and Computational Biology ( http://zmb.univie.ac.at/en/structure-of-the-zmb/department-of-structural-and-computational-biology/ ) of the Max F. Perutz Laboratories ( https://www.mfpl.ac.at ) of the University of Vienna as well as the Laura Bassi Center for Optimized Structural Studies.
For information on Djinovic-Carugo’s research group, see: http://www.mfpl.ac.at/djinovic
Original publication: E. d. A. Ribeiro, N Pinotsis, A Ghisleni, A Salmazo, P. V. Konarev, J. Kostan, B. Sjoeblom, C. Schreiner, A. A. Polyansky, E. A. Gkougkoulia, M. R. Holt, F. L. Aachmann, B. Žagrović, E. Bordignon, K. F. Pirker, D. I. Svergun, M. Gautel and K. Djinović-Carugo: The structure and regulation of human muscle α-actinin. Cell 158, 1447 – 1460, Dec. 04, 2014 DOI: http://dx.doi.org/10.1016/j.cell.2014.10.056
Link to the publication: http://www.cell.com/cell/abstract/S0092-8674(14)01428-7
Prof. Kristina Djinovic-Carugo
Max F. Perutz Laboratories University of Vienna Department of Structural and Computational Biology Campus Vienna Biocenter 5
1030 Vienna, Austria
M +43 / 664 / 602 77 522 03
Austrian Science Fund FWF:
Haus der Forschung
1090 Vienna, Austria
T +43 / 1 / 505 67 40 - 8111
Copy Editing & Distribution:
PR&D – Public Relations for Research & Education Mariannengasse 8
1090 Vienna, Austria
T +43 / 1 / 505 70 44
Marc Seumenicht | PR&D – Public Relations for Research & Education
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