The Structure of Bovine Lysosomal α-Mannosidase Suggests a Novel Mechanism for Low-pH Activation

Lysosomal α-mannosidase (LAM: EC 3.2.1.24) belongs to the sequence-based glycoside hydrolase family 38 (GH38). Two other mammalian GH38 members, Golgi α-mannosidase II (GIIAM) and cytosolic α-mannosidase, are expressed in all tissues. In humans, cattle, cat and guinea pig, lack of lysosomal α-mannosidase activity causes the autosomal recessive disease α-mannosidosis. Here, we describe the three-dimensional structure of bovine lysosomal α-mannosidase (bLAM) at 2.7 Å 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 α-mannosidosis at the atomic level. The atomic coordinates and structure factors have been deposited in the Protein Data Bank (accession codes 1o7d and r1o7dsf).