Many neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are characterised by protein aggregation, clumps of misfolded proteins. Currently these diseases cannot be cured, and the mechanisms causing them are not yet fully understood. Cells mobilise, however, so-called chaperones, important proteins that can prevent other proteins from misfolding and clumping together into aggregates. Some chaperones are known to also break up aggregates.
"Thorough investigation to look at chaperon function"
By carefully scrutinising a handful of studies from several different projects around the world, researchers at the Departments of Biology and Biological Engineering at Chalmers and the Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, have compiled data on the chaperone function of peroxiredoxins in various organisms.
“We have made a thorough investigation to look at what characterises this 'new' and relatively uncharacterised function of peroxiredoxins at the molecular and structural level. In this review we spotted great similarities, but also important differences to previously known chaperones,” says Mikael Molin, researcher in systems biology at Chalmers.
Two molecule structure exposes necessary surfaces
A certain type of molecular chaperones, so called small heat-shock proteins, can change their shape in a controlled fashion. So do the peroxiredoxins. Under normal conditions, 10 enzyme molecules associate to form a ring. However, under certain conditions, two rings can assemble into oligomers containing 20 molecules. Previous studies have linked these double rings to the chaperone function.
“In our review, we could see that the formation of double ring structures is not enough to induce the chaperone function. Instead, data from both our own research and that of others, suggest that the double rings must also fall apart, into multiple structures containing only two molecules. These structures may expose surfaces that are needed to bind other proteins and to prevent them from aggregating,” says Mikael Molin.
In the short term, Mikael Molin believes that this provides ideas for new hypotheses about how the peroxiredoxins could slow down neurodegenerative diseases and aging.
In the long term, this research can generate knowledge that could be used in drug development or the development of biomarkers that with higher precision will find dietary and lifestyle factors stimulating healthy aging (i.e. free from dementia and cancer).
Text: Susanne Nilsson Lindh
More about the chaperon function
Read the scientific article: Structural determinants of multimerization and dissociation in 2-Cys peroxiredoxin chaperone function
- In terms of structure and function peroxiredoxins mostly resemble the small heat-shock proteins (Hsp), a class of small chaperones that carry out important functions under heat-stress
- In terms of function chaperones can be divided into holdases and foldases. Holdases bind unfolded parts of proteins and prevent them from sticking together, while foldases use energy from the cells’ energy currency ATP in different ways to counteract protein aggregation.
- Similar to some small heat-shock proteins peroxiredoxins assemble into oligomers that have been associated to chaperone activity. They can also, like holdase chaperones, bind unfolded parts of proteins and in this way prevent them from aggregating.
- Dissociation of the high molecular weight peroxiredoxin oligomers seems to be necessary for efficient resolution of aggregated proteins and dissociation is linked to the function of an ATP-dependent enzyme called sulfiredoxin. Further studies are, however, necessary to ascertain the exact structural changes involved in the function of peroxiredoxins as chaperones.