Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A protein safeguards against cataracts

24.10.2013
Activation mechanism of a protective protein in the ocular lens resolved

The refractive power of the human eye lens relies on a densely packed mixture of proteins. Special protective proteins ensure that these proteins do not clump together as time passes.


Storage form (24-mer) and active forms of aB-crystallin which protect against cataract

When this protective mechanism fails, the ocular lens becomes clouded – the patient develops a cataract. Scientists at the Technische Universitaet Muenchen (TUM) have now resolved the activation mechanism of one of these protective proteins, laying the foundation for the development of new therapeutic alternatives.

The lens of the human eye is made up of a highly concentrated protein solution that imparts the eye its high refractive power. Yet, despite this high protein content the ocular lens must remain clear and transparent. To this end ocular lens cells have developed a remarkable strategy: They have thrown overboard the complex machinery present in all other cells of the human body for building up and breaking down proteins. Instead, lens proteins are created only once in a lifetime – during embryonic development. They are as old as the organism itself. To make them last a lifetime, the proteins are kept permanently in a dissolved state. If they clump together, the lens clouds over and the patient gets cataracts.

Alternative to surgery

To date, this condition could only be treated surgically by replacing the clouded lens with an artificial one. However, if the precise mechanism by which lens proteins are kept in a dissolved state were understood, it would open up new avenues for treatment. So, how does the cell manage to keep the proteins soluble for so long? The magic lies in two proteins, αA-crystallin and its relative, αB-crystallin. They are the best-known representatives of the class of so-called small heat shock proteins. They play an important role in all human cells, since they prevent other proteins from turning into useless clumps when subjected to strong heat or cell stress.

What exactly these protective proteins look like and how they act remained shrouded in mystery for a long time, in spite of intensive research. “The great challenge in the analysis of these two crystallin types lies in their inordinate variety,” explains Johannes Buchner, professor for biotechnology at the Technische Universitaet Muenchen. “These proteins exist as a mixture of very different forms, each comprising a variable number of subunits. This makes it very difficult to distinguish the individual structures from one another.”

Molecular switch

In 2009, in very close collaboration with Sevil Weinkauf, professor for electron microscopy at the Technische Universitaet Muenchen, the first part of the αB-crystallin puzzle fell into place. The team successfully deciphered the molecular structure of the most important form of this versatile protein – a molecule comprising 24 subunits. Under normal conditions, i.e. when the cell is not exposed to stress, this complex is the most common variant. However, it is merely an idle form that contributes little to the prevention of clumping in other proteins. It was clear that there must be another molecular switch that triggers the protective protein.

It is this trigger mechanism that the team headed by Buchner and Weinkauf uncovered now. When a cell is exposed to stress, for instance when subjected to heat, phosphate groups are attached to a specific region of the protein. The negative charges of these phosphates break the links between the subunits and the large complexes consequently disintegrate into numerous smaller ones of only six or twelve subunits each. As a result of this breakup, the regions at the ends of the complexes become more flexible allowing the molecules to dock up with different partners, thereby preventing them from clumping – the protective protein is now active.

Interdisciplinary cooperation

The success of the scientists can be traced back above all to the interdisciplinary combination of biochemical and electron-microscopic methodologies. Aligning the information from the two-dimensional protein disintegration images with the manifold three-dimensional structures of αB-crystallin proved particularly difficult. “Imagine you only have a few pictures of a coffee cup’s shadow cast and want to infer the shape of the cup from that,” Weinkauf explains to illustrate the problem. “Now, if you think that sounds difficult, try to imagine you have not just a single cup, but a cupboard full of china that you want to deduce from the shadow casts. It is precisely this daunting challenge that we met for αB-crystallin.”

The newly acquired insights into the αB-crystallin mode of action form a solid footing for new therapeutic approaches. For instance, medication to treat cataracts could be developed: it would trigger the αB-crystallin activation mechanism to clear up clouded ocular lenses. But αB-crystallin also plays a role in other tissue cells. In cancer cells, for example, it is overly active and interferes with the so-called programmed cell death. In this case new medication would aim at inhibiting the protein.

The work has been funded by German Research Foundation (Cluster of Excellence Center for Integrated Protein Science Munich (CIPSM) and SFB 1035).

Publications:

Jirka Peschek, Nathalie Braun, Julia Rohrberg, Katrin Christiane Back, Thomas Kriehuber, Andreas Kastenmüller, Sevil Weinkauf and Johannes Buchner: Regulated structural transitions unleash the chaperone activity of αB-Crystallin, PNAS Early Edition, 2013

Contact:

Prof. Johannes Buchner
Technische Universität München
Department of Chemistry
Lichtenbergstraße 4, 85748 Garching, Germany
Tel.: +49 89 289 13340
Fax: +49 89 289 13345
E-Mail
Prof. Sevil Weinkauf
Tel.: +49 89 289 – 13517
Fax: +49 89 289 - 13521

Dr. Andreas Battenberg | EurekAlert!
Further information:
http://www.tum.de

Further reports about: human eye protective protein three-dimensional structure

More articles from Life Sciences:

nachricht Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

Im Focus: Computer-Designed Customized Regenerative Heart Valves

Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.

Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...

Im Focus: Light-induced superconductivity under high pressure

A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.

Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Supersonic waves may help electronics beat the heat

18.05.2018 | Power and Electrical Engineering

Keeping a Close Eye on Ice Loss

18.05.2018 | Information Technology

CrowdWater: An App for Flood Research

18.05.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>