The structure of bovine lysosomal alpha-mannosidase suggests a novel mechanism for low-pH activation

J Mol Biol. 2003 Mar 28;327(3):631-44. doi: 10.1016/s0022-2836(03)00172-4.


Lysosomal alpha-mannosidase (LAM: EC belongs to the sequence-based glycoside hydrolase family 38 (GH38). Two other mammalian GH38 members, Golgi alpha-mannosidase II (GIIAM) and cytosolic alpha-mannosidase, are expressed in all tissues. In humans, cattle, cat and guinea pig, lack of lysosomal alpha-mannosidase activity causes the autosomal recessive disease alpha-mannosidosis. Here, we describe the three-dimensional structure of bovine lysosomal alpha-mannosidase (bLAM) at 2.7A resolution and confirm the solution state dimer by electron microscopy. We present the first structure of a mammalian GH38 enzyme that offers indications for the signal areas for mannose phosphorylation, suggests a previously undetected mechanism of low-pH activation and provides a template for further biochemical studies of the family 38 glycoside hydrolases as well as lysosomal transport. Furthermore, it provides a basis for understanding the human form of alpha-mannosidosis at the atomic level. The atomic coordinates and structure factors have been deposited in the Protein Data Bank (accession codes 1o7d and r1o7dsf).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cattle
  • Crystallography, X-Ray
  • Databases as Topic
  • Dimerization
  • Drosophila melanogaster
  • Enzyme Activation
  • Glycoside Hydrolases / chemistry
  • Glycosylation
  • Hydrogen Bonding
  • Hydrogen-Ion Concentration
  • Kidney / enzymology
  • Lysosomes / enzymology*
  • Lysosomes / metabolism
  • Mannose / metabolism
  • Mannosidases / chemistry*
  • Microscopy, Electron
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • alpha-Mannosidase


  • Glycoside Hydrolases
  • Mannosidases
  • alpha-Mannosidase
  • Mannose

Associated data

  • PDB/1O7D