Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Chikwana, Vimbai M.; Khanna, May; Baskaran, Sulochanadevi; Tagliabracci, Vincent S.; Contreras, Christopher; DePaoli‐Roach, Anna A.; Roach, Peter J.; Hurley, Thomas D.

doi:10.1073/pnas.1310106111

Cited by 31 publications

(34 citation statements)

References 35 publications

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“…This mechanism has been challenged (27), but it is supported by other independent experiments. Glycogen synthase can catalyze the formation of the fast ester from UDP-glucose in vitro (41), and by x-ray crystallography, the active site of glycogen synthase can accommodate fast ester and its cognate reaction product UMP (41). A similar pathway might account for phosphorylation at C3, but there is no supporting evidence (26).…”

Section: Discussionmentioning

confidence: 99%

Glycogen Phosphomonoester Distribution in Mouse Models of the Progressive Myoclonic Epilepsy, Lafora Disease

DePaoli‐Roach

Contreras

Segvich

et al. 2015

Journal of Biological Chemistry

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Background: Lafora disease is characterized by abnormal, hyperphosphorylated glycogen. Results: 20% of the total phosphate is present as a C6 phosphomonoester of glucose residues; this proportion is unchanged in glycogen from mouse models of Lafora disease. Conclusion: C6 phosphate is not the dominant phosphomonoester. Significance: C2, C3, or C6 phosphate could all contribute to aberrant glycogen structure.

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Section: Discussionmentioning

confidence: 99%

Glycogen Phosphomonoester Distribution in Mouse Models of the Progressive Myoclonic Epilepsy, Lafora Disease

DePaoli‐Roach

Contreras

Segvich

et al. 2015

Journal of Biological Chemistry

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“…This reordered segment pushes the arginine regulatory helices apart from each other across the subunit interface and coincidently induces large scale translational and rotational movements of the subunits that promote better access for glycogen chains to reach the catalytic site 10 . These conformational transitions that lead to opening of the tetrameric interfaces are critical in order to permit full closure of the N-terminal domain upon the C-terminal domain and generate the catalytically competent ternary complex between the enzyme and both the donor and acceptor substrates 14 .…”

Section: Introductionmentioning

confidence: 99%

Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation

et al. 2016

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Glycogen synthase (GS) is the rate limiting enzyme in the synthesis of glycogen. Eukaryotic GS is negatively regulated by covalent phosphorylation and allosterically activated by glucose-6-phosphate (G6P). To gain structural insights into the inhibited state of the enzyme, we solved the crystal structure of yGsy2-R589A/R592A to a resolution of 3.3 Å. The double mutant has an activity ratio similar to the phosphorylated enzyme and also retains the ability to be activated by G6P. When compared to the 2.88 Å structure of the wild-type G-6-P activated enzyme, the crystal structure of the low-activity mutant showed that the N-terminal domain of the inhibited state is tightly held against the dimer-related interface thereby hindering acceptor access to the catalytic cleft. Based on these two structural observations, we developed a reversible redox regulatory feature in yeast GS by substituting cysteine residues for two highly conserved arginine residues. When oxidized, the cysteine mutant enzyme exhibits activity levels similar to the phosphorylated enzyme, but cannot be activated by G-6-P. Upon reduction, the cysteine mutant enzyme regains normal activity levels and regulatory response to G-6-P activation.

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“…Glycogen clearly contains monoester phosphate on the C2, C3, and C6 positions and laforin is definitively a glycogen phosphatase, but the origin of that phosphate is unknown [53–55]. Some suggest that C2 and perhaps C3 phosphate is due to a metabolic error by glycogen synthase [54,56,57]. Alternatively, others have proposed that a kinase similar to GWD phosphorylates glycogen, but no candidate has been reported [53].…”

Section: Discussionmentioning

confidence: 99%

Structural biology of glucan phosphatases from humans to plants

Gentry

Brewer

Kooi

2016

Current Opinion in Structural Biology

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Glucan phosphatases are functionally conserved at the enzymatic level, dephosphorylating glycogen in animals and starch in plants. The human glucan phosphatase laforin is the founding member of the family and it is comprised of a carbohydrate binding module (CBM) domain followed by a dual specificity phosphatase (DSP) domain. Plants encode for two glucan phosphatases: Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2). SEX4 contains a DSP domain followed by a CBM domain, while LSF2 contains a DSP domain and lacks a CBM. This review demonstrates how glucan phosphatase function is conserved and highlights how each family member employs a unique mechanism to bind and dephosphorylate glucan substrates.

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Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Cited by 31 publications

References 35 publications

Glycogen Phosphomonoester Distribution in Mouse Models of the Progressive Myoclonic Epilepsy, Lafora Disease

Glycogen Phosphomonoester Distribution in Mouse Models of the Progressive Myoclonic Epilepsy, Lafora Disease

Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation

Structural biology of glucan phosphatases from humans to plants

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