A preliminary 3D model for ISD11 protein

HERRERA, M.G; SANTOS, J.; ROMÁN, E.A

Conferencia; 4th International Society for Computational Biology Latin America Bioinformatics Conference (ISCB-LA); 2016

Iron-sulfur clusters are cofactors present in all known forms of life. In eukaryotic organisms, the small protein ISD11 that belongs to the LYR family is a central piece in the cluster assembly. This small protein is essential: R68L mutation result in deficiencies in oxidative phosphorylation in patients, while F40A, I72A E84A are lethal in cellular models. Interestingly, ISD11 has no homolog in bacteria. The three-dimensional structure of ISD11 is unknown, probably as a result of its unexpected insolubility. In this work we combined computational and experimental approaches to build a preliminary model of ISD11 tertiary structure. To this end we used residue-residue contact predictions to constrain coarse-grained molecular dynamic simulations. The models obtained were compared with De Novo models obtained using Robetta, I-tasser and RaptorX. Secondary structure was inspected using Agadir algorithm, suggesting a dependence of stability on pH that is in agreement with the high content of R and K residues. This information was taken into account to design a strategy for ISD11 purification and refolding. Preliminary results suggest that the recombinant protein produced in E. coli can be properly refolded. The protein exhibits high content of helical structure and aromatic residues in a substantially rigid environment, commonly observed in the native-state ensembles of globular proteins. Protein-protein interactions between ISD11 and other members of the Fe-S cluster assembly protein complex may be inferred from the information shared by the protein chains. Here we will discuss the results obtained