EMBL Hamburg News
“What has it got in its pocketsses?”- the first structure of the family of nematode fatty acid and retinoid binding proteins
A ribbon representation of the structure of FAR7 from C. elegans. The numbering of the
alpha-helices as well as the entrance to the two pockets (P1 and P2) are shown.
In a recent paper published in the Journal of Biological Chemistry, scientists at EMBL-Hamburg describe the first protein structure of a family of nematode lipid binding proteins (LBPs). The work, led by Rosie Jordanova in the Tucker group, provides the basic structural and functional information for investigation of inhibitors of lipid binding by fatty acid and retinoid binding (FAR) proteins.
Parasitic nematodes cause serious diseases in humans and animals, and have a negative economic impact on agricultural industries. Prophylactic treatment offers short-term benefits, but due to the rapid development of drug resistance in parasites, there is a pressing need for novel treatments of nematode infections. Lipid binding proteins (LBPs) play an important role in the limited lipid metabolism of parasitic nematodes, and therefore could be suitable targets for anti-nematode drugs.
Jordanova and co-workers have now described the first high resolution structure of a fatty acid and retinoid binding (FAR) protein, the 1.8 Å crystal structure of Ce-FAR-7. Ce-FAR-7 has nine helices, packed into a novel fold containing two hydrophobic binding pockets, which accommodate different types of cargo. Pocket P1 can accommodate fatty acids with different lengths of the aliphatic chain, whereas P2 is more suitable for bulkier ligands such as retinoids and other signaling lipids. The results suggest that retinol binding can be up-regulated by casein kinase 2, via phosphorylation of Thr26 positioned near the bottom of the pocket P2. In collaboration with the group of Prof. Liebau at the University of Münster, GFP localization in vivo shows that Ce-FAR-7 is intracellular and present in all developmental stages of the nematode. It is mainly localized in the excretory cell and head hypodermis region of the worm. However, during starvation, its localization changes and Ce-FAR-7 is expressed in the body hypodermis. It is hoped that these results will form the basis for a new generation of anti-nematode drugs.