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

The clan 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 clan includes five enzymes implicated in lysosomal storage diseases: β-glucuronidase (Sly disease), β-glucocerebrosidase (Gau-cher disease)...

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Bibliographic Details
Published in:Glycobiology (Oxford) 1997-03, Vol.7 (2), p.277-284
Main Authors: Durand, Patrick, Lehn, Pierre, Callebaut, Isabelle, Fabrega, Sylvie, Henrissat, Bernard, Mornon, Jean-Paul
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding Sites
Cluster Analysis
Conserved Sequence
Glycoside Hydrolases - chemistry
Glycoside Hydrolases - classification
glycosyl hydrolases
Humans
hydrophobic cluster analysis
lysosomal storage diseases
Lysosomes - enzymology
Molecular Sequence Data
Protein Structure, Secondary
Protein Structure, Tertiary
Sequence Analysis - methods
Sequence Homology, Amino Acid
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Summary:The clan 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 clan includes five enzymes implicated in lysosomal storage diseases: β-glucuronidase (Sly disease), β-glucocerebrosidase (Gau-cher disease), β-galactosidase (Landing disease and Morquio type B disease), β-mannosidase (mannosidosis) and α-L-iduronidase (Hurler-Scheie disease). Examination of known 3D structures from some families of the clan 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 clan. Our results reveal that, despite low levels of sequence identity, all the proteins of the clan (including the aforementioned lysosomal enzymes) likely share a similar catalytic domain consisting of an (α/β)8 barrel with conserved functional amino acids located at the C-terminal ends of six of the eight strands constituting the β-barrel. Interestingly, several mutations reported to be responsible for lysosomal storage diseases are located within these conserved regions of the lysosomal enzyme catalytic domains.
ISSN:0959-6658
1460-2423
DOI:10.1093/glycob/7.2.277