Active-site motifs of lysosomal acid hydrolases: Invariant features of clan GH-A glycosyl hydrolases deduced from hydrophobic cluster analysis

The dan GH-A is a group of more than 200 proteins representing nine established families of glycosyl hydrolases that act on a large variety of substrates. This dan includes five enzymes implicated in lysosomal storage diseases: beta-glucuronidase (Sly disease), beta-glucocerebrosidase (Gaucher disease), beta-galactosidase (Landing disease and Morquio type B disease), beta-mannosidase (mannosidosis) and alpha-L-iduronidase (Hurler-Scheie disease). Examination of known 3D structures from some families of the dan allowed us to deduce structural and functional features shared by these proteins. We then used the hydrophobic cluster analysis method to study the protein sequences of the entire dan. Our results reveal that, despite low levels of sequence identity, all the proteins of the dan (including the aforementioned lysosomal enzymes) likely share a similar catalytic domain consisting of an (alpha/beta)(8) barrel with conserved functional amino acids located at the C-terminal ends of six of the eight strands constituting the beta-barrel. Interestingly, several mutations reported to be responsible for lysosomal storage diseases are located within these conserved regions of the lysosomal enzyme catalytic domains.