Protein yields secrets, and cancer target?

The discovery of how the protein - called vinculin - changes its shape in order to fulfil its cellular functions is helping to answer some major questions about the life of cells, the development of tissues and organs and the spread of cancer from one part of the body to another, according to scientists at St Jude Children's Research Hospital in the US.

In the online report, which will appear in the printed journal on 8 January, the scientists describe how slight changes in the shape of vinculin completely change its role in the cell. For example, by alternately changing its shape from active to inactive forms, vinculin can control the cell's ability to remain stationary or move through its environment.

Vinculin enables cells to move within developing tissues and organs of the embryo and spark the healing of wounds. But it can also regulate the ability of cancer cells to move away from tumours and spread cancer to other parts of the body, according to Tina Izard of St Jude's department of haematology-oncology.

The discovery of how vinculin changes its shape holds promise for developing new ways to prevent the spread of cancer cells, she said.

The study also reveals the extent to which a cell can modify its activity using proteins - i.e. independently of its genetic material. It was already known that cells can read certain genes in different ways to make different proteins, but the new findings reinforce the regulatory role that proteins themselves play in cell functions.

The researchers used X-ray crystallography to generate information on the shape of vinculin in its inactive and active forms. Izard's team shot X-rays at crystalline forms of human vinculin and collected the patterns formed when the X-rays diffracted off the different parts of the protein. The diffraction patterns underwent computer processing using software developed at Global Phasing Limited, a company in Cambridge, UK.

They found that vinculin changes its shape by moving the individual helical 'cylinders' making up its head (Vh) in a process which the team has called helical bundle conversion, Izard said.

The team demonstrated that when a protein called talin binds to Vh, it changes shape in a way that is critical to the protein's ability to anchor itself to the extracellular matrix outside the cell membrane This keeps the cell in one spot so it does not drift away.

However, when the protein called alpha-actinin binds to Vh, a different shape follows and this plays a critical role in stabilising a chain of molecules called cadherin. This extends through the cell membrane and binds with cadherin chains from neighbouring cells. The connection means cells can bind together into sheets, and thus form tissues and organs.

Together, talin and a-actinin help vinculin build tissues and organs out of individual cells by keeping cells in one spot, Izard said. But when vinculin shifts from active to inactive form and back again, the cell can perform other tasks.

For example, such a shift lets many cells move from their original location to take up positions elsewhere in the developing body where new tissues and organs are destined to arise.

It is possible that drugs which prevent this could be used to bind cancer cells to the primary tumour site. This could have the benefit of preventing the metastasis of tumour cells to distant sites in the body.