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



: Heikinheimo P, Helland R, Leiros HKS, Leiros I, Karlsen S, Evjen G, Ravelli R, Schoehn G, Ruigrok R, Tollersrud OK, McSweeney S, Hough E

Publisher: ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD

: 2003

JOURNAL OF MOLECULAR BIOLOGY

: J MOL BIOL

: 327

: 3

: 631

: 644

: 14

: 0022-2836

DOI: https://doi.org/10.1016/S0022-2836(03)00172-4


Lysosomal alpha-mannosidase (LAM: EC 3.2.1.24) 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 2.7 Angstrom 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). (C) 2003 Elsevier Science Ltd. All rights reserved.



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