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Structure of Penicillium citrinum α1,2-Mannosidase Reveals the Basis for Differences in Specificity of the Endoplasmic Reticulum and Golgi Class I Enzymes*

Y. Lobsanov,F. Vallée,A. Imberty,Takashi Yoshida,P. Yip,A. Herscovics,P. Howell

Published 2002 in Journal of Biological Chemistry

ABSTRACT

Class I α1,2-mannosidases (glycosylhydrolase family 47) are key enzymes in the maturation of N-glycans. This protein family includes two distinct enzymatically active subgroups. Subgroup 1 includes the yeast and human endoplasmic reticulum (ER) α1,2-mannosidases that primarily trim Man9GlcNAc2 to Man8GlcNAc2 isomer B whereas subgroup 2 includes mammalian Golgi α1,2-mannosidases IA, IB, and IC that trim Man9GlcNAc2 to Man5GlcNAc2 via Man8GlcNAc2 isomers A and C. The structure of the catalytic domain of the subgroup 2 α1,2-mannosidase fromPenicillium citrinum has been determined by molecular replacement at 2.2-Å resolution. The fungal α1,2-mannosidase is an (αα)7-helix barrel, very similar to the subgroup 1 yeast (Vallée, F., Lipari, F., Yip, P., Sleno, B., Herscovics, A., and Howell, P. L. (2000) EMBO J. 19, 581–588) and human (Vallée, F., Karaveg, K., Herscovics, A., Moremen, K. W., and Howell, P. L. (2000) J. Biol. Chem. 275, 41287–41298) ER enzymes. The location of the conserved acidic residues of the catalytic site and the binding of the inhibitors, kifunensine and 1-deoxymannojirimycin, to the essential calcium ion are conserved in the fungal enzyme. However, there are major structural differences in the oligosaccharide binding site between the two α1,2-mannosidase subgroups. In the subgroup 1 enzymes, an arginine residue plays a critical role in stabilizing the oligosaccharide substrate. In the fungal α1,2-mannosidase this arginine is replaced by glycine. This replacement and other sequence variations result in a more spacious carbohydrate binding site. Modeling studies of interactions between the yeast, human and fungal enzymes with different Man8GlcNAc2 isomers indicate that there is a greater degree of freedom to bind the oligosaccharide in the active site of the fungal enzyme than in the yeast and human ER α1,2-mannosidases.

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