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PS: It’s not cholesterol

Disease-related proteins carry surprising cargo

In a nutshell:

– Group of proteins don’t carry cholesterol after all
– Requires re-thinking diseases the proteins have been linked to
– New method for taking proteins from the cell with their lipid cargo still attached

How our body processes cholesterol has a well-known impact on our health, but it turns out that another ‘fat molecule’ – or lipid – may be at the heart of some diseases which were thought to involve cholesterol. A group of proteins linked to conditions such as metabolic syndrome and some cancers don’t carry cholesterol as was supposed, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered in work published today in Nature.

“Our findings mean the disease doesn’t involve cholesterol, but another lipid: phosphatidylserine,” says Anne-Claude Gavin, who led the work.

Until now, scientists thought the proteins Osh6 & Osh7 carried sterols – cholesterol and other similar lipids – around the cell, because those proteins are very similar to ones that are known to do so. But Kenji Maeda from Gavin’s lab found that they carry phosphatidylserine (PS) instead. They ferry PS from where it is produced inside the cell to where it is needed at the cell membrane – an important task, since if PS ends up in the wrong place on a mammalian cell membrane, it can cause coagulation and programmed cell death. 

“I expected some surprises, but nothing as big as this,” says Maeda: “I thought maybe we’d find a protein carried a slightly different lipid, but PS and sterol? There’s almost no similarity.”

The findings were doubly surprising, as scientists thought PS wasn’t transported by proteins, but by vesicles. Gavin, Maeda and colleagues first made their surprising discovery when examining all the lipid-transporting proteins in yeast cells, as a test of a new approach they developed to fish proteins out of a cell with any lipids they carry still attached. 

When the EMBL scientists looked at the equivalent human protein, they found that it also binds to PS rather than to cholesterol. The result opens up new paths for investigating the causes of a variety of diseases that this and other similar proteins have been linked to. It has also spiked the researchers’ curiosity. Gavin and colleagues are now planning to expand from the half-dozen proteins that carry lipids in yeast cells to a similar study of their hundreds of counterparts in human cells. “I think we may have interesting surprises,” Gavin says.

This work was carried out in collaboration with Marko Kaksonen’s lab at EMBL.

Tags: cholesterol, lipid

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