Structure and function of Class I alpha 1,2-mannosidases involved in glycoprotein synthesis and endoplasmic reticulum quality control.
Class I alpha 1,2-mannosidases (glycosylhydrolase family 47) are conserved through eukaryotic evolution. This protein family comprises three subgroups distinguished by their enzymatic properties. The first subgroup includes yeast (Saccharomyces cerevisiae) and human alpha 1,2-mannosidases of the endoplasmic reticulum that primarily form Man(8)GlcNAc(2) isomer B from Man(9)GlcNAc(2). The second subgroup includes mammalian Golgi alpha 1,2-mannosidases, as well as enzymes from insect cells and from filamentous fungi, that trim Man(9)GlcNAc(2) to Man(8)GlcNAc(2) isomers A and/or C intermediates toward the formation of Man(5)GlcNAc(2). Yeast and mammalian proteins of the third subgroup have no enzyme activity with Man(9)GlcNAc(2) as substrate. The members of subgroups 1 and 3 participate in endoplasmic reticulum quality control and promote proteasomal degradation of misfolded glycoproteins. The yeast endoplasmic reticulum alpha 1,2-mannosidase has served as a model for structure-function studies of this family. Its structure was determined by X-ray crystallography as an enzyme-product complex. It consists of a novel (alpha alpha)(7) barrel containing the active site that includes essential acidic residues and calcium. The structures of the subgroup 1 human endoplasmic reticulum alpha 1,2-mannosidase and of a subgroup 2 fungal alpha 1,2-mannosidase were determined by molecular replacement. Comparison of the enzyme structures is providing some insight into the reasons for their different specificities.
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McGill Cancer Centre, McGill University, 3655 Promenade Sir William Osler, Montréal, H3G 1Y6, Québec, Canada. snnette@med.mcgill.ca
D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008322:Mammals; D008361:Mannosidases / Q000737:chemistry / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship
D006023:Glycoproteins; D008361:Mannosidases; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase