The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis

Mutations in palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme th at removes fatty acyl groups from cysteine residues in modified proteins, c ause the fatal inherited neurodegenerative disorder infantile neuronal cero id lipofuscinosis. The accumulation of undigested substrates leads to the f ormation of neuronal storage bodies that are associated with the clinical s ymptoms. Less severe forms of PPT1 deficiency have been found recently that are caused by a distinct set of PPT1 mutations, some of which retain a sma ll amount of thioesterase activity. We have determined the crystal structur e of PPT1 with and without bound palmitate by using multiwavelength anomalo us diffraction phasing. The structure reveals an alpha/beta-hydrolase fold with a catalytic triad composed of Ser115-His289-Asp233 and provides insigh ts into the structural basis for the phenotypes associated with PPT1 mutati ons.