Highlighted Paper: Structural analysis of human FANCL, the E3 ligase in the fanconi anemia pathway.

The Protein Structure Function Laboratory, headed by Helen Walden published this paper in the Journal of Biological Chemistry.

The Fanconi Anemia pathway is essential for DNA damage repair. The pathway comprises approximately 15 genes, mutations in which give rise to Fanconi Anemia, a rare childhood disease with a high incidence of cancers. At the heart of the pathway is the protein FANCL which is responsible for the modification of FANCI and FANCD2 with ubiquitin. This provides the signal for the DNA repair proteins.  Last year determined the three-dimensional atomic structure of FANCL from the fruit fly, Drosophila melanogaster.  

The fly pathway is much more simple than the human system, containing only 5 of the known components. Our objective in this study was to determine as much of the human protein structure as currently possible, and compare it with the fly protein in order to determine the differences between the systems, and the impact those differences may have. In order to do this, we employed protein crystallography and biochemical techniques. We have found that globally the proteins are quite similar, thereby validating the use of the fly system as a model for the more complex human system. However, there are significant differences in the surface composition of the proteins which could explain the requirement for additional components in humans.

We have also narrowed down which regions of the protein are responsible for interaction with the various binding partners.  Understanding the differences between the 2 systems may enable us to develop rationales for stabilising the human protein in its more complex environment.