Ohno_2010_Brain.Dev_32_524

To elucidate the basis of neuronal ceroid lipofuscinosis 1 (CLN1) from the viewpoint of enzyme structure, we constructed structural models of mutant palmitoyl protein thioesterase 1 (PPT1) proteins using molecular modeling software, jackal and TINKER. We classified the amino acid substitutions responsible for CLN1 and divided them into two groups, groups 1 and 2, based on the biochemical phenotype. Then, we examined the structural changes in the PPT1 protein for each group by calculating the solvent-accessible surface area (ASA) and the number of atoms affected. Our results revealed that the structural changes in group 1, which exhibits a complete deficiency of PPT1 activity, were generally large and located in the core region of the enzyme molecule. In group 2 exhibiting residual PPT1 activity, the structural changes in PPT1 were smaller and localized near the surface of the enzyme molecule. Coloring of affected atoms based on the distances between those in the wild type and mutants revealed the characteristic structural changes in the PPT1 protein geographically and semi-quantitatively. Structural investigation provides us with a deeper insight into the basis of CLN1.