Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Strong Evidence – New Insight in Muscle Function

27.04.2015

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.


In a muscle every protein has to pull its weight. Thanks to high-resolution structural analysis the role of the essential muscle protein α-Actinin is now better understood.

© Gautel / Ghisleni / Pinotsis / Djinovic-Carugo

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


Scientific Contact:
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
E kristina.djinovic@univie.ac.at
W https://www.mfpl.ac.at

Austrian Science Fund FWF:
Marc Seumenicht
Haus der Forschung
Sensengasse 1
1090 Vienna, Austria
T +43 / 1 / 505 67 40 - 8111
E marc.seumenicht@fwf.ac.at
W http://www.fwf.ac.at

Copy Editing & Distribution:
PR&D – Public Relations for Research & Education Mariannengasse 8
1090 Vienna, Austria
T +43 / 1 / 505 70 44
E contact@prd.at
W http://www.prd.at

Marc Seumenicht | PR&D – Public Relations for Research & Education

Further reports about: Biology Cell Computational Biology FWF Muscle Protein disorders function muscle protein

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>