18 September 2006

Insulin mystery cracked after 20 years

By
Cosmos Online
How insulin - one of the body's most important hormones - interacts with a cell is governed by the shape of the insulin receptor, and this shape has been a mystery to scientists for more than two decades. Now Australian researchers have cracked its secret.
Insulin mystery cracked after 20 years

Colin Ward in his lab at Australia's national research agency, the CSIRO. Credit: CSIRO

SYDNEY: How insulin – one of the body’s most important hormones – interacts with a cell is governed by the shape of the insulin receptor, and this shape has been a mystery to scientists for more than two decades. Now Australian researchers have cracked its secret.

The hormone insulin controls when and how sugar is used in the body. A deficiency in insulin production can lead to diabetes, a condition that affects more than 1 million Australians. This number is expected to rise as the Australian population becomes older and fatter.

In the British journal Nature, Colin Ward of CSIRO Molecular and Health Technologies revealed the shape of the protein sitting outside the cell that binds to insulin. According to Ward, this discovery “has given us a lot of insight into how insulin might work”.

It is the protein’s folds, coils, twists, and contours that govern its interaction with insulin. Much like the key to your front door fits perfectly with its lock and no others, an insulin receptor is like the lock and insulin is like the key. It is the complex shape of the insulin receptor that the Australian team, from a division of the national science agency CSIRO, has managed to work out.

“What we’ve managed to do is something that people have been wanting to know for a very long time,” said Ward. “The receptor was first identified in 1970, its sequence was published in Nature in 1985, some fifteen years later. The 3-D structure of the part [of the insulin receptor] that sits inside the cell… was published in 1994. It’s taken us another twelve years to finally get the picture of the other half.”

The protein making up the receptor was grown in cells and then isolated, purified and crystallised. The crystals were then bombarded with beams of x-rays and data about the protein’s make-up was gradually assembled and interpreted until a full picture of the structure emerged. This is a common method for determining the structure of a protein.

However, the insulin receptor is no ordinary protein. It is about 200 times bigger than insulin itself, it is actually two identical molecules intertwined, and it has various chemicals in it that made it nearly impossible to crystallise. “It is a very sensitive molecule,” said Ward. “The big problem is getting the crystals. Once you get the crystal, the process of solving the structure is actually straightforward.”

Now that the structure is known, drugs and chemicals that mimic insulin have become a possibility. “It is a holy grail and many people say it can’t be done. They might be right. But that to a scientist is like a red rag to a bull. Let’s go and show them that it can.”

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