The study of cancer causing proteins could now be improved thanks to researchers in Germany who have synthesised fully functional lipid modified K-Ras proteins.

Herbert Waldmann and colleagues at the Max Planck Institute in Dortmund have synthesised fully functional lipid 

modified K-Ras proteins using a technique called expressed protein ligation (EPL). Ras type GTP-ases are a superfamily of proteins that regulate cellular processes such as growth, division and cell death. The K-Ras isoform is mutated in many cancers. In order to function, Ras proteins must be modified at the start of their amino acid chain, their so-called C-terminus. EPL allows a large peptide unit to be linked to a modified peptide via a thioester group at its C-terminus.

Protein-protein interactions in Ras signalling have been widely studied. However, little information is known about alterations, such as the attachment of lipoproteins on interaction with cell membranes, to the protein after it is has been folded. Native bonds, the same types of bonds as present in the cell, are needed in synthetic models to study these interactions.

Waldmann and colleagues expressed the K-Ras protein core in E.coli, and attached synthetic lipopeptides to serve as membrane anchors. The modified protein is fully functional, contains exclusively native amide bonds, and interacts with cell components in the same way as the native protein. 'The presence of the native linkage between both moieties makes it possible to further approximate the natural context of cellular signal transduction,' said Waldmann.

Katherine Vickers