Thursday, 30 October 2008

What are heat shock proteins?

The story all started like this:

In 1962 someone at the Genetics Institute in Pavia, Italy, turned up the temperature in an incubator holding fruit flies. When Ferruccio Ritossa, then a young geneticist, examined the cells of these “heat shocked” flies, he noticed that their chromosomes had puffed up at discrete locations. The puffy appearance was a known sign that genes were being activated in those regions to give rise to their encoded proteins, so those sites of activity became known as the heat shock loci [and their proteins became known as heat shock proteins].

Since then, heat shock proteins have been discovered in almost all cellular life, and are among the oldest molecules to have been conserved by evolution. Despite their importance they are poorly, if understandably, named - which was why I quoted the above explanatory passage (found here) at the outset. A much better name for the class of proteins would be stress proteins, since they are apparently induced in increased numbers by a whole array of stressors, such as hypoxia, toxin exposure, ultraviolet light, infections, and (of course) heat. In fact, some researchers prefer to call the proteins by this very name.

The role of heat shock proteins becomes more clear if you consider some of the perils of protein formation. The genetic code of a protein (DNA and then RNA) only tells the assembly machinery which amino acid to slot in next. It doesn't - directly - tell the protein how to assume its unique and complicated 3D structure. Yet the right 3D structure is everything for a protein - it defines to a large extent what the protein is capable of.

So how do proteins get their 3D structures? Largely, it is the forces between the various amino acids, in multiple areas, that forces the chain to assume its particular knot-like shape. ('Knot-like' indeed: take a look at a relatively simple protein - G-actin.) For instance, if two amino acids repel each other (perhaps because of electrostatic forces), they will move further apart. The opposite holds for amino acids that attract one another. Furthermore, hydrophobic amino acids tend to 'want' to be in the centre of the protein, away from the water around it, whereas hydophilic amino acids 'want' the reverse.

By itself, this is often enough to construct the proteins' 3-dimentionality. But sometimes this isn't enough, and the protein needs extra help. Enter the 'heat shock proteins', which seem to act as 'chaperones' for developing proteins. They help the folding of the developing protein and assist in stabilising protein-to-protein interactions.

This explains why some heat shock proteins seem to be permanently expressed - they are always needed for certain proteins. On the other hand, it also provides a reason why their expression is vastly up-regulated under conditions of stress. As the author quoted above notes:

Under emergency conditions, such as extreme heat or cold, oxygen deprivation, dehydration or starvation, a cell would be struggling just to survive. Critical proteins might be degraded by the harsh environment, even as the cell would try to churn out replacements. In these circumstances, heat shock proteins would mitigate the stress by rescuing essential proteins, dismantling and recycling damaged ones, and generally keeping cell operations running as smoothly as possible. Hence, when a cell is under high stress, one of its first responses will be to manufacture more of the HSPs [heat shock proteins] themselves, as Ritossa first witnessed 46 years ago.

Finally, heat shock proteins seem to play an important role in immunity (binding to an antigen and helping its presentation to our immune cells) as well as a poorly identified role in the cardiovascular system. The area of heat shock proteins is undergoing heavy research and much intellectual upheaval, apparently, so expect to hear more about these guys in the near future.

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