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

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Glycogen is a glucose polymer that contains minor amounts of covalently attached phosphate. Hyperphosphorylation is deleterious to glycogen structure and can lead to Lafora disease. Recently, it was demonstrated that glycogen synthase catalyzes glucose- phosphate transfer in addition to its characteristic glucose transfer reaction. Glucose-1,2-cyclic-phosphate (GCP) was proposed to be formed from UDP-Glc breakdown and subsequently transferred, thus providing a source of phosphate found in glycogen. To gain further insight into the molecular basis for glucose-phosphate transfer, two structures of yeast glycogen synthase were determined; a 3.0-Å resolution structure of the complex with UMP/GCP and a 2.8-Å resolution structure of the complex with UDP/glucose. Structural superposition of the complexes revealed that the bound ligands and most active site residues are positioned similarly, consistent with the use of a common transfer mechanism for both reactions. The N-terminal domain of the UDP·glucose complex was found to be 13.3° more closed compared with a UDP complex. However, the UMP·GCP complex was 4.8° less closed than the glucose complex, which may explain the low efficiency of GCP transfer. Modeling of either α- or β-glucose or a mixture of both anomers can account for the observed electron density of the UDP·glucose complex. NMR studies of UDP-Glc hydrolysis by yeast glycogen synthase were used to verify the stereochemistry of the product, and they also showed synchronous GCP accumulation. The similarities in the active sites of glycogen synthase and glycogen phosphorylase support the idea of a common catalytic mechanism in GT-B enzymes independent of the specific reaction catalyzed.

Original languageEnglish (US)
Pages (from-to)20976-20981
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number52
DOIs
StatePublished - Dec 24 2013

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Glycogen Synthase
Glycogen
Phosphates
Uridine Diphosphate
Glucose
Yeast
Uridine Monophosphate
Uridine Diphosphate Glucose
Glycogen Phosphorylase
Stereochemistry
Glucans
Carrier concentration
Hydrolysis
Nuclear magnetic resonance
Ligands
glucopyranose-1,2-cyclic phosphate
Enzymes

Keywords

  • Crystallography
  • Glycosyltransfer

ASJC Scopus subject areas

  • General

Cite this

Structural basis for 2'-phosphate incorporation into glycogen by glycogen synthase. / Chikwana, Vimbai M.; Khanna, May; Baskaran, Sulochanadevi; Tagliabracci, Vincent S.; Contreras, Christopher J.; DePaoli-Roach, Anna; Roach, Peter J.; Hurley, Thomas D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 52, 24.12.2013, p. 20976-20981.

Research output: Contribution to journalArticle

Chikwana, Vimbai M. ; Khanna, May ; Baskaran, Sulochanadevi ; Tagliabracci, Vincent S. ; Contreras, Christopher J. ; DePaoli-Roach, Anna ; Roach, Peter J. ; Hurley, Thomas D. / Structural basis for 2'-phosphate incorporation into glycogen by glycogen synthase. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 52. pp. 20976-20981.
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