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Proteins Like Origami

Proteins Like Origami


When I was 19, I had a summer job in a hospital laboratory in Sherbrooke, Quebec. The hospital was fairly small, as it served an English community of perhaps 20,000 to 30,000 people in the extended region.

The director of the lab, a pathologist, took a keen interest in the summer students. Every day when he examined biopsies and other pathological specimens, he invited the summer students to come and watch. He then explained in detail what he was observing and later he told us the diagnosis.

I remember very clearly a crumbly white tissue from a post mortem. The patient’s internal organs had turned to this crumbly material. The diagnosis was amyloidosis, now believed to result from the abnormal folding of proteins. I remember asking if there was a cure. There was none. The cause of this condition was unknown.

We still don’t know very much, but scientists are keenly interested in diseases caused by misfolded proteins. What we are learning is how narrow the boundary is between good health and serious diseases.

Altogether, scientists now estimate that incorrect folding of proteins is the cause of some twenty diseases. Among these, the most infamous include Cruetzfeldt-Jakob disease (the human equivalent of BSE), Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as ALS or amyotrophic lateral sclerosis. More common protein misfolding diseases include late-onset diabetes when protein fibrils destroy the islets of Langerhans in the pancreas, and cataracts.

Not surprisingly, many research projects have focused on the issue of protein folding. Why does the normal process sometimes go wrong? The results to date provide considerable food for thought. The production of desirable versions of proteins is nowhere near as automatic as we might have imagined.

The first piece of bad news was the discovery that many proteins can assume a disease-causing fibril shape. In other words, the familiar proteins which normally exhibit highly complex shapes (linked to their functions in the cell), can on certain occasions, adopt a thread-like form called amyloid fibrils. The fibrils typically clump into plaque.

Previous to this discovery, cell biologists had believed that there is only one possible shape which any given protein can assume. It was the order of amino acids in the protein molecule (like beads strung end to end) which dictated how the protein would fold and what the final shape would be. Now however, it appears that a given protein can assume alternative shapes.

What, one might wonder, causes a given protein to ever assume the preferred shape? Apparently correct protein folding is made possible by elaborate mechanisms in the living cell. It is not a process left to chance.

In order to manufacture enough molecules of a needed protein in the cell, many tiny molecular machines simultaneously produce long chains of amino acids. Since space within the cell is extremely limited, the result is that many identical protein chains, already partly folding, but still long and gangly, will accumulate within touching distance of one another. However these chains must not touch, because if they do, they will form non-functioning clumps.

The cell must segregate these lengthening chains from each other. The special devices to do this are called molecular chaperones. These provide a private environment within which each molecule will fold properly. More than 50 families of molecular chaperones are known. One family, called the chaperonins, includes the GroEL-GroES chaperon, which has been particularly well studied.

This GroEL-GroES molecular machine is a somewhat barrel-shaped structure with openings at both ends. Both the size of the cage and surface charge on the inside surface, are ideal for speeding up the folding of a number of different protein chains. Once a protein chain is sequestered inside the cavity at one end, a lid (GroES molecule) clamps the barrel shut.

The protein chain then has 10-15 seconds to fold inside the cage before a chemical reaction causes the lid to come off, the protein to emerge, and a new chain to enter at the opposite end, now clamped inside by another molecular lid. Thus protein molecules are alternately processed at opposite ends of the barrel.

An additional feature to the barrel is that upon release of a folded molecule, that end of the cage becomes smaller and the other end becomes larger. The whole thing is an endless see-saw effect.

The beauty of the chaperone system is that it prevents proteins from misfolding and clumping into fibrils, which is one of the hazards of concentrated protein molecules. A recent discussion of the GroEL-GroES chaperone, concludes with terms which suggest the input of planning and purpose (design) into the system thereby hinting at the action of personality: “It is a testament to the ingenuity of natural selection that the chaperonin cage not only combats aggregation caused by crowding outside the cage but also uses crowding to accelerate protein folding inside the cage. Nanoengineers trying to improve the yield of therapeutic proteins could profit from studying the tricks of the chaperonin nanocage.” (Nature June 27/06 p. 362). Since “natural selection” is a process which cannot show personality or any other personal attribute, they more appropriately might have used the word “designer” instead.

In view of the fact that protein folding is so complicated, and by no means automatically correct, scientists ask themselves how unwanted protein association into fibrils is normally avoided in living systems. We now know, after all, that amyloid-like fibril formation is encouraged when the concentration of a protein rises in a tissue either as a result of the breakdown of cellular machinery regulating protein synthesis, or as a result of the breakdown of machinery which expedites the recycling of unwanted protein molecules.

It is a further disturbing fact that protein molecules which are already completely folded, can be induced to refold into an abnormal fibril form if the protein concentration is too high. Moreover, a study on tiny round worms, reported in Nature February 16/06 (p. 767), found that the presence of a few fibrils of one protein was enough to prompt seven other proteins, normally stable, to misfold. The result was fatal for the worms.

Mutations, of course, are another factor which can lead to misfolded proteins and serious disease. An article in Nature (September 7/06) describes a case in mice. Scientists unexpectedly discovered a mutation which resulted in one amino acid occasionally being substituted for another amino acid when proteins are produced. The frequency of this substitution is only once in 500 situations where the first amino acid is called for. The end result of this small error is protein misfolding, accumulation of protein aggregates and progressive degeneration of the mouse nervous system. This study led to the realization that the line between a tolerable degree of error and a catastrophic loss of accuracy in protein synthesis is very narrow, and that the margin of error in protein composition is smaller than previously believed. (p. 42)

It is apparent that the thing which characterizes a healthy cell is precisely designed molecular machines in good working order. The idea that almost any protein can form amyloid fibrils is shocking to many, because it indicates that good design is what is required for health rather than spontaneous chemistry. Good health is a gift not to be taken for granted. Even in the small details within the cell, are we not wonderfully designed?

Margaret Helder
December 2006

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