After nine years of research, chemists of Utrecht University together with colleagues in Europe and America have solved the mystery of how one of the most important chaperone proteins in our cells, Hsp90, selects its client proteins. Hsp90 plays a role in nearly all processes in our cells, as well as in the origin of diseases such as Alzheimer disease, cancer and cystic fibrosis. Insight into the binding process of Hsp90 will increase our understanding of the origin of these diseases, thereby opening new avenues to prevent or cure them. The results of the research were published in Cell on 27 February.
Chaperone proteins are important machines in a cell's protein factory. They assist in the production new proteins and are responsible for quality control of existing proteins. "Many diseases develop as a result of a malfunction of proteins in our cells, such as clogging of damaged proteins. The chaperones are our first line of defense," explains project leader Dr Stefan Rüdiger of Utrecht University.
An entirely different principle
Hsp90’s binding principle had researchers baffled for a long time, because of the different types of protein to which it binds. Rüdiger: "Other chaperone proteins have a defined cavity that allows recognition of short sequences, which you can compare to a barcode. Researchers were unable to find such a general barcode reader in Hsp90."
This prompted researchers to change their approach. They ingeniously managed to visualise Hsp90 binding to a protein with an atypical shape, the Tau protein. They discovered that Hsp90 actually spreads a large number of weak binding contacts across a large surface area. This is, in fact, also allows reading a barcode, albeit with an entirely different binding principle from any other chaperone proteins.
Insight into the protein factory
The clarification of this principle has provided researchers with more insight into a cell's protein factory. For instance, they now understand why in the folding process of certain proteins, Hsp70 chaperones provide assistance first and Hsp90 acts later. Furthermore, it is now also clear how the chaperones scan the barcodes of the proteins they need. "One surprising aspect is that the proteins that need chaperone proteins to be able to fold display the same barcodes as the proteins that only enter for inspection, such as the Tau protein," says Rüdiger.
These insights will increase our understanding of the origin of diseases, such as Alzheimer disease. Alzheimer disease is caused by clumping of the Tau protein. Clumped Tau proteins damage brain cells.
Now that it is clear how Hsp90 binds to the Tau protein, Rüdiger wants to study how Hsp90 influences the decision-making process about what happens to the Tau protein next, and what may be the consequences for the origin of Alzheimer disease. "We think that the Tau protein’s binding to Hsp90 can result in one of three things. First of all, the connection is broken and the Tau protein continues its work in the cell. Secondly, the Tau protein is rendered for destruction. Thirdly, the Tau protein starts to clump, causing Alzheimer's disease. The question is how Hsp90 influences the switch between these three options."
Hsp90 is also known to act as a chaperone protein for a number of signalling proteins that are essential to the development of tumour growth. Therefore, in the past twenty years, researchers have been studying drugs that block Hsp90 in order to delay or stop the growth of tumours. This research has now reached the stage in which drugs are already close to the clinic.
The discovery of Hsp90's binding principle makes it possible to develop more specific drugs to target this chaperone protein. These drugs may also curb the progress of Alzheimer’s disease. However, further research is still needed, according to Rüdiger.
Hsp90-Tau complex reveals molecular basis for specificity in chaperone action
1Karagöz GE, 1Duarte AMS, Akoury E, 1Ippel H, Biernat J, 1Morán Luengo T, 1Radli M, 1Didenko T, Nordhues BA, Veprintsev DB, Dickey CA, Mandelkow E, Zweckstetter M, 1Boelens R, 1Madl T and 1Rüdiger SGD
Cell, 27 February, DOI http://dx.doi.org/10.1016/j.cell.2014.01.037
1 (At the time of the research) Employed at Utrecht University.
This research was supported by two Marie Curie Grants awarded to Stefan Rüdiger and by the European BioNMR project, awarded to Professor Rolf Boelens.
· Dr Stefan Rüdiger, Department of Chemistry/Bijvoet Center, Faculty of Science, S.G.D.Rudiger@uu.nl, +31 (0)6 81 90 71 18.
· For other questions: Monica van der Garde, Press Officer of the Faculty of Science, +31 6 13 66 14 38, firstname.lastname@example.org.