β-
Mannosidase is a lysosomal
enzyme from the glycosyl
hydrolase family 2 that cleaves the single β(1-4)-linked
mannose at the nonreducing end of
N-glycosylated proteins, and plays an important role in the
polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β-
mannosidase, can lead to the
lysosomal storage disease β-
mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β-
mannosidase in both the apo- and
mannose-bound forms. The structure is similar to previously determined β-
mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other
ligand-bound β-
mannosidases from bacterial and fungal sources where bound
sugars were in a boat-like conformation, we find the
mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of
therapeutics for treating diseases caused by β-
mannosidase deficiency. DATABASE: Structural data are available in the
Protein Data Bank under the accession numbers 6DDT and 6DDU.