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Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis. We have captured crystallographic snapshots of human glycogenin during its reaction cycle, revealing a dynamic conformational switch between ground and active states mediated by the sugar donor UDP-glucose. This switch includes the ordering of a polypeptide stretch containing Tyr195, and major movement of an approximately 30-residue "lid" segment covering the active site. The rearranged lid guides the nascent maltosaccharide chain into the active site in either an intra- or intersubunit mode dependent upon chain length and steric factors and positions the donor and acceptor sugar groups for catalysis. The Thr83Met mutation, which causes glycogen storage disease XV, is conformationally locked in the ground state and catalytically inactive. Our data highlight the conformational plasticity of glycogenin and coexistence of two modes of glucosylation as integral to its catalytic mechanism.

Original publication

DOI

10.1073/pnas.1113921108

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

12/12/2011

Volume

108

Pages

21028 - 21033

Addresses

Structural Genomics Consortium, Old Road Research Campus Building, Oxford, United Kingdom OX3 7DQ.

Keywords

Humans, Glycogen, Glucosyltransferases, Glycoproteins, Crystallography, X-Ray Diffraction, Protein Conformation, Mutation, Missense, Models, Molecular