Researchers at the University of Texas Medical School at Houston showed that phospholipids, which make up the permeable barrier of cell membranes, play a direct role in the folding of membrane proteins – proteins that penetrate the membrane or bind to either side of it.

William Dowhan and colleagues looked at how a protein called GabP, which transports an amino acid across the membrane of the bacterium E. coli, is affected by the presence of a phospholipid named phosphatidylethanolamine ( PE ).

Phospholipids, unlike their fatty acid and cholesterol cousins, include a phosphate group that spurs them to form a bilayer with water-friendly outer layers sandwiching an impermeable water-unfriendly inner layer that defines the outer surface of cells. Transport of nutrients and waste material across the cell membrane is then governed by the specific proteins associated with it.

In a strain of E. coli lacking phosphatidylethanolamine, the GabP protein misfolded, with two areas of the protein inverting from their normal structure. The PE-lacking protein's amino acid transfer rate plummeted to nearly zero, falling 99 percent compared to the transfer rate in unaltered E. coli with PE.

GabP is the third membrane protein that Dowhan and colleagues have shown to be affected by the presence of PE.

The team is using the E. coli model to discover how all proteins fold in the membrane, not just transport proteins such as GabP but also biosynthetic proteins that manufacture complex compounds such as proteins and fats out of simple compounds.

" The next goal now that we've defined the phenomenon is to get into the specifics, find the mechanisms by which these proteins fold. What part of the protein interacts with the lipid, and what part of the lipid with the protein ? " said Dowhan.

Understanding the molecular basis for membrane protein folding will help researchers address serious diseases caused by misfolded proteins. " In cystic fibrosis, Alzheimer's disease and mad cow disease, the dysfunctional proteins are associated with membranes," Dowhan said.

Membrane proteins make up 30 percent of known proteins. Dowhan estimates another 40 percent are loosely tied to membranes. "So you are looking at possibly 70 percent of biology occurring at or in a lipid membrane surface," Dowhan said.

Membranes and their surface proteins are accessible targets for pharmaceuticals, and most drugs target either membrane proteins on human cells or the membranes of pathogens.

Source: University of Texas Health Science Center, 2005


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