The mystery unfolds ...

Cracking the 'folding' code of protein molecules could help us to tackle such diseases as Alzheimer's, says Simon Hadlington

Britain's relationship with Europe, the potential health of the population, and the future of the cattle-farming industry may all hang on the kinks and bends in a molecule present in the brain. The best scientific hypothesis at present is that mad cow disease and its human analogue, Creutzfeldt-Jakob disease, are caused by a misshapen variant of a naturally occurring protein which corrupts its correctly configured neighbours by causing them to buckle out of shape.

To demonstrate the importance and difficulty of protein folding, Sheena Radford goes to a cupboard at one end of her compact office in Leeds University's Department of Biochemistry and produces a large sheet of paper, perhaps two feet square. The paper is heavily creased and is criss- crossed with red and blue lines, creating myriad geometric patterns.

Dr Radford says she had made an origami model from the sheet of paper, had unfolded it and marked all the creases.

"If I asked you to go away and fold this piece of paper along the creases and lines which are already marked on it, without highly detailed instructions, the chances are that you would not be able to make the original model very quickly."

She returns to the cupboard. "In fact, if you fold that piece of paper correctly, it becomes this," she says, triumphantly emerging with a small, neat and surprisingly rigid model of a flat-bottomed boat.

Dr Radford's demonstration is impressive and one that she uses in her lectures as an analogy to what happens in living cells, where the folding of protein molecules - a kind of molecular origami - is fundamental to life. And even the most skilled origamist would look clumsy and slow compared to Mother Nature, who can fold a complex protein molecule spontaneously and with utter precision.

Dr Radford's pioneering work on protein folding, largely carried out during eight years at the Oxford Centre for Molecular Sciences (five as a Royal Society University Research Fellow) and being continued at Leeds, has earned her the Biochemical Society's 1996 Colworth Medal, awarded each year to a scientist under the age of 35 who has made major contribution to biochemistry. It is the first time a woman has won the medal.

The award reflects the strength of British research in what is one of the hottest topics in biomedical science.

The central role proteins play in living organisms is difficult to overstate. Not one activity characteristic of life could occur in the absence of these ubiquitous substances. Indeed, the function of DNA, the genetic matter contained in each living cell, is to tell the cell which proteins to manufacture. Once the proteins have been created, they, in effect, do the rest to keep the show on the road.

But unlike DNA, with its elegantly simple double-helix configuration, proteins come in an infinity of shapes and sizes, and the three-dimensional form of a protein is largely responsible for its function. If the shape is wrong, the protein will not be able to do its job.

"When the folding process fails to work properly the consequences can be catastrophic," says Dr Radford. "The list of diseases whose cause can be pinpointed to proteins misfolding is growing almost daily - from cataracts to Alzheimer's disease and cystic fibrosis."

For the past 25 years biochemists have been trying to understand how proteins fold up in nature. It is a hugely complex problem and progress is painstaking. But the intricate mechanics that take place in the living cell are slowly being unravelled and a picture is beginning, gradually, to emerge.

"Cracking the folding code will have wide implications," says Dr Radford, "such as the design for new and novel proteins for use in biotechnology and medicine. By understanding the driving forces of folding we may be able to overcome or avoid many disease states."

In the cell, proteins are manufactured in molecular factories called ribosomes, using plans derived from the cell's DNA.

Proteins are made up of a string of individual molecules, amino acids. As the newly formed chain of amino acids comes off the production line, it is swathed by other proteins whose job it is to protect the delicate newborn protein from the harsh environment of the cell.

Because of their protective role, these proteins are called "molecular chaperones". In Dr Radford's laboratory one particular chaperone is currently of interest. It is a large structure (in molecular terms) shaped like two doughnuts stacked together, which encapsulates the nascent protein within its central cavity. Here, the new protein can safely twist and bend until it reaches its correct shape before it is transported to its final destination within the cell.

The way in which the protein folds is governed by many factors, not all of them understood. For the past 25 years it has been known that the most important determinant of the protein's shape is the sequence in which the different amino acids have been strung together. In fact, it was this discovery, by Chris Anfinsen in the United States, which opened up the whole field of protein folding, and which won Anfinsen a Nobel Prize in 1972.

Dr Radford's approach to the folding conundrum has been to take proteins whose amino acid sequence is known, to "unfold" them in a test-tube and then to allow them spontaneously to re-fold.

Using a variety of analytical tricks it is possible to follow the re- folding and map it on a computer.

The aim of the work is to derive a set of "ground rules" that govern the folding process: to be able to state that a given sequence of amino acids, under a particular set of circumstances, will fold into a predictable three-dimensional shape.

"Then we will need to learn the ways by which the molecular chaperones ensure that these events can take place in a living cell," says Dr Radford. "Only when we understand both these facets will we be able to paint a complete picture of Nature's origami."

Such a picture, when it finally emerges, will be a huge asset in developing new ways of tackling the ever-growing list of debilitating "folding diseases".

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