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Deciphering Protein Folding: The Devil Is in the Details

Por: | 13 de enero de 2014

Atomium_Culture_Protein_Chain

By Stefano Gianni, University of Rome La Sapienza

Proteins control the life of every living cell down to the smallest detail. For example, almost every reaction taking place in our body is under the control of a specific protein. The oxygen in our blood is transported by a protein and much of our cells are built with proteins.

These molecules exert their power through two distinct features: their chemistry and their three-dimensional shape. We know plenty about the chemistry of proteins, but the mechanism by which proteins fold up to their given shape is one of the biggest questions in science. In less than a second, a protein can fold into the correct structure. The speed of protein folding is quite amazing: imagine solving a Rubik’s cube in less than a second! Protein folding has a much higher number of possible combinations and yet folding is almost always successful.

Occasionally, however, proteins fold incorrectly and get trapped in the wrong shape. These faulty proteins can run amok and cause pathological conditions such as Parkinson’s disease, Alzheimer’s disease and mad cow disease.

Living cells can use several mechanisms to protect themselves from the negative effects of misfolded proteins. For example, the cell can quarantine misfolded proteins into a confined area, where the fault may be repaired or the protein degraded. To distinguish between folded and misfolded proteins, the cell uses a quality control system that relies on various sensor molecules able to detect incorrect folding. If a misfolded protein escapes this quality control system, it may damage the cell and eventually cause disease.

Although many of the components of this quality control system have been identified, little is known about the actual ‘fingerprint’ of misfolding. In other words, what factors trigger the quality control system? What kind of folding defects are recognised?

Scientists have been studying the mechanisms of protein folding for about 50 years, yet very little is known about the mysteries of protein misfolding, the origin of several pathological conditions. The best way to unveil the molecular detail of the protein folding process is to apply the basic rules of chemistry: first identify all the intermediate shapes between the starting reactants — the raw materials — and the products of the reaction, then figure out their structure. But the elusive nature of protein folding intermediates and the high speed of the folding reaction make this task extremely complicated. Even the most detailed experimental study on protein folding to date could only provide one or two snapshots of the changes in structure that take place during the transformation to a folded protein. No information was uncovered on misfolding events.

My research group in the Department of Biochemical Sciences at the University of Rome – La Sapienza is focusing on the folding of a simple protein family, the PDZ domain. Until recently, the PDZ domain was thought to fold via a specific and well-controlled mechanism. We have revealed that misfolding can occur even in this class of protein. Misfolded PDZ domain proteins are peculiarly stable, so they can be maintained in a test tube for long enough to study, and the sequence of events that produces a correctly folded protein and the pathway that generates an incorrectly folded protein are neatly separate and distinct. These characteristics make PDZ domain proteins a great protein family to study and our group has been the first to characterise the misfolding process.

Surprisingly, misfolding relies on a very small perturbation of the correctly folded structure. This minuscule change is responsible for ruining the folding process of the entire protein, so the folding pathway must be followed down to the last instruction in order to produce a working protein. The key to protein folding is indeed in the details!

Researchers have now not only characterised the misfolded structure of PDZ domain proteins but have also managed to isolate it. By studying the isolated proteins we can find out all sorts of information about the incorrect shape, which will prove crucial when it comes to designing drugs to prevent the diseases caused by misfolding.

This research into PDZ domains represents the first structural characterisation of a misfolded protein, the precursor of various diseases. Although we don’t yet know whether the type of misfolding observed in PDZ domains also occurs in other proteins, the first milestone has now been reached. Identifying this structure paves the way for future work on tackling protein misfolding and gives new hope for possible strategies to prevent it and the diseases it causes.

 

Stefano Gianni
University of Rome La Sapienza
www.atomiumculture.eu

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