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.

Source Article

Maeda, K. Anand, K., Chiapparino, A., Kumar, A., Poletto, M., Kaksonen, M. & Gavin, A.C. Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins. Published online in Nature on 11 August 2013. DOI: 10.1038/nature12430

Article Abstract

The internal organization of eukaryotic cells into functionally specialized, membrane-delimited organelles of unique composition implies a need for active, regulated lipid transport. Phosphatidylserine (PS), for example, is synthesized in the endoplasmic reticulum (ER), and then preferentially associates - through not fully elucidated mechanisms - with the inner leaflet of the plasma membrane (PM). Lipids can travel via transport vesicles. Alternatively, several protein families known as lipid-transfer proteins (LTPs) can extract a variety of specific lipids from biological membranes and transport them, within a hydrophobic pocket, through aqueous phases. Here, we report the development of an integrated approach that combines protein fractionation and lipidomics to characterize the LTP-lipid complexes formed in vivo. We applied the procedure to 13 LTPs in the yeast Saccharomyces cerevisiae: the six Sec14 homology (Sfh) proteins and the seven oxysterol-binding homology (Osh) proteins. We found that Osh6 and Osh7 have an unexpected specificity for PS. In vivo, they participate in PS homeostasis and the transport of this lipid to the PM. Our finding represent the first direct evidence for the non-vesicular transfer of PS from its site of biosynthesis (the ER) to its site of biological activity (the PM). The structure of Osh6 bound to PS reveals unique features that are conserved among other metazoan OSBPs and are required for PS recognition. We describe a new subfamily of oxysterol-binding proteins (OSBPs) - including human ORP5 and ORP10 - that transfer PS and propose new mechanisms of action for a protein family that is involved in several human pathologies such as cancer, dyslipidaemia or metabolic syndrome. 

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