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'Mix and match' proteins found

September 8, 2006 By Kerri Smith This article courtesy of Nature News.

Rearranged peptides may play big role in immunity.

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Proteins seem to be more changeable than biologists once thought. Human cells can apparently shuffle the components of these molecules dicing them up and reordering them to make new structures.

This ability might allow the body to boost our immune response against infected cells. And researchers are optimistic that it could enhance their understanding of how the immune system recognizes cells that need to be attacked.

DNA codes for proteins by first producing an RNA template, which can be chopped up and reassembled depending on which specific version of a protein is needed. Biologists had long assumed that once this mixing was done at the RNA level, the proteins made were set in stone.

But in 2004, researchers found that this wasn't always true at least not for proteins found in skin-cancer cells. Some of these molecules seemed to have been cut up, had sections removed, and then been glued back together1. Such 'protein surgery' has also been seen in plants and single-celled organisms.

Now Edus Warren of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues show that even more chopping and changing occurs in proteins found in some normal cells. In this week's Science2, they show that proteins can be cut up, rearranged and glued back together, vastly increasing the number of different structures that can be made from an original protein. And as this was seen in proteins that are found in normal cells, it suggests that such rearrangements might be far more common than had been appreciated.

For the chop

The team studied a group of short proteins called peptides, which are found on the surface of cells. These molecules are used by components of the immune system called T cells to determine whether a cell is normal or a foreign invader.

The peptides are generally formed when the proteins made inside the cell are degraded: a piece of cell machinery called the proteasome chews up proteins and spits out these chunks. But the proteasome has other tricks too. "The proteasome can splice peptides together," says Warren. "Every once in a while, new peptide bonds will be created, not just destroyed."

It isn't clear why this happens, or what the newly spliced peptides do. But as the molecules end up on the cell's surface, they are probably involved in the cell's "immunologic identity", says Warren.

In the latest study, peptides made in this 'mix and match' fashion were found on cells from a leukaemia patient who had received a bone-marrow transplant. The patient's rearranged peptides unfortunately triggered an immune reaction from the T cells in the transplanted marrow. The rearranged proteins are of a type commonly found in many cells, including non tumorous ones.

Self-defence

The researchers speculate that peptide splicing might also help the immune system to recognize cells that have been invaded by a virus. As they replicate inside a cell, viruses create new peptides on the cell's surface. If that cell could then rearrange these peptides, it might increase the immune system's chance of recognizing the foreign invader, they say. This idea has not been tested.

It is not yet known whether all cells use their proteasomes to shuffle all types of proteins, or whether the mechanism is specific to peptides used by the immune system. Warren suspects that the mechanism will be found elsewhere. "There is no reason why cells could not have learned how to use this mechanism to their advantage. But I don't think that people have ever looked," he says.

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References

  1. Vigneron N., et al.Science, 304. 587 - 590 (2004).
  2. Warren E. H., et al. Science, 313. 1444 - 1447 (2006).

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