A protein safeguards against cataracts

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. 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 αβ-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.