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Cancer researchers find new 'helix of helix' structure in protein folding

It's the first time the particular structure, called a supra-helix, has been seen in natural proteins. The study was published in the Journal of Molecular Biology and funded by Cancer Research UK.

The researchers – a team of structural biologists from The Institute of Cancer Research, London – were investigating a huge protein called the anaphase-promoting complex (APC/C), which helps control the final phase of cell division.

Although some of the roles of APC/C are still poorly understood, it is known to play a key part in how cells make copies of themselves in all animals as well as 'lower' organisms such as yeast, which is what the researchers were studying. It's also involved in preventing cells from becoming cancerous, and malfunctioning APC/C is associated with human colon cancer.

In a series of painstaking experiments using computer modelling, crystallography and high power electron microscopy, the researchers discovered that sub-units of APC/C attach together in sets of two similar proteins, called homo-dimers.

When the researchers mixed sets of homo-dimers together, they found that they naturally stuck together to form a spiral which spun around on itself, forming a spiral of a spiral – or a supra-helix.

To imagine the structure, think of a long spiral staircase. Then, imagine the staircase being wound like a piece of string into another long spiral. Viewed from above, the larger helix has a hole in the middle, like a doughnut.

At very high powers of magnification, the scientists were able to see that there are 10 sub-units – homo-dimers – for each turn in the secondary helix. Each sub-unit twists by about 35 degrees relative to its neighbour.

A double helix, which is how DNA arranges itself, is very different, with two single spirals wound together and connected by 'rungs', like a twisted ladder.

Professor David Barford, who led the study as Professor of Molecular Biology at The Institute of Cancer Research before taking up a new position at the Medical Research Council Laboratory of Molecular Biology in Cambridge, said: "Our study has given us important insights into the structure of APC/C, a protein complex involved in several different aspects of cell division which also plays an important role in cancer. We worked out that sub-units of APC/C fit together in twos before fixing to each other in a helix which in turn winds around itself to form a second-order structure, called a supra-helix.

"Importantly, we also showed that previous studies were incorrect in suggesting a different structure for one protein sub-unit of the complex, called Apc7. We showed that Apc7 behaves like three other APC/C sub-units – called Cdc23, Cdc16 and Cdc27 – all of which we found docked into the larger complex in a similar way."

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