Title : The crystal
structure of palmitoyl protein thioesterase-2 (
PPT2 ) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases,
PPT1 and
PPT2
Abstract :
- Mutations in palmitoyl protein thioesterase-1 ( PPT1 ) have been found to cause the infantile form of neuronal ceroid lipofuscinosis, which is a lysosomal storage disorder characterized by impaired degradation of fatty acid-modified proteins with accumulation of amorphous granular deposits in cortical neurons, leading to mental retardation and death
- Palmitoyl protein thioesterase-2 ( PPT2 ) is a second lysosomal hydrolase that shares a 26% identity with PPT1
- A previous study had suggested that palmitoyl-CoA was the preferred substrate of PPT2
- Furthermore, PPT2 did not hydrolyze palmitate from the several S-palmitoylated protein substrates
- Interestingly, PPT2 deficiency in a recent transgenic mouse model is associated with a form of neuronal ceroid lipofuscinosis, suggesting that PPT1 and -2 perform non-redundant roles in lysosomal thioester catabolism
- In the current paper, we present the crystal structure of PPT2 at a resolution of 2.7 A. Comparisons of the structures of PPT1 and -2 show very similar architectural features; however, conformational differences in helix alpha4 lead to a solvent-exposed lipid-binding groove in PPT1
- The limited space between two parallel loops (beta3-alphaA and beta8-alphaF) located immediately above the lipid-binding groove in PPT2 restricts the binding of fatty acids with bulky head groups, and this binding groove is significantly larger in PPT1
- This structural difference accounts for the ability of PPT2 to hydrolyze an unbranched structure such as palmitoyl-CoA but not palmitoylcysteine or palmitoylated proteins
- Furthermore, differences in fatty acid chain length specificity of PPT1 and -2, also reported here, are explained by the structure and may provide a biochemical basis for their non-redundant roles