Abstract
Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.
Highlights
Glycogen is a branched glucose polymer and serves as an important energy store
glycogen debranching enzyme (GDE) is highly conserved in animals and fungi[7]
Molecular insights into the GT and GC catalysis
Summary
Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. This process comes to a halt four residues before the branch point, making glycogen/starch debranching an essential step in its mobilization In humans, this reaction is catalysed by glycogen debranching enzyme (GDE)[1,2]. GDE is highly conserved in animals and fungi[7] It is distinct from enzymes participating in glycogen/starch debranching in bacteria and plants. In combination with functional characterizations of the GDE disease-causing mutations, these studies provide molecular insights into GSDIII
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