Structural basis for glucose-6-phosphate activation of glycogen synthase

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Regulation of the storage of glycogen, one of the major energy reserves, is of utmost metabolic importance. In eukaryotes, this regulation is accomplished through glucose-6-phosphate levels and protein phosphorylation. Glycogen synthase homologs in bacteria and archaea lack regulation, while the eukaryotic enzymes are inhibited by protein kinase mediated phosphorylation and activated by protein phosphatases and glucose-6-phosphate binding. We determined the crystal structures corresponding to the basal activity state and glucose-6-phosphate activated state of yeast glycogen synthase-2. The enzyme is assembled into an unusual tetramer by an insertion unique to the eukaryotic enzymes, and this subunit interface is rearranged by the binding of glucose-6-phosphate, which frees the active site cleft and facilitates catalysis. Using both mutagenesis and intein-mediated phospho-peptide ligation experiments, we demonstrate that the enzyme's response to glucose-6-phosphate is controlled by Arg583 and Arg587, while four additional arginine residues present within the same regulatory helix regulate the response to phosphorylation.

Original languageEnglish
Pages (from-to)17563-17568
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number41
DOIs
StatePublished - Oct 12 2010

Fingerprint

Glycogen Synthase
Glucose-6-Phosphate
Phosphorylation
Enzymes
Inteins
Archaea
Eukaryota
Catalysis
Glycogen
Mutagenesis
Protein Kinases
Ligation
Arginine
Catalytic Domain
Yeasts
Bacteria
Peptides
Proteins

Keywords

  • Allosteric activation
  • Glycosyltransferase

ASJC Scopus subject areas

  • General

Cite this

@article{7117e26e9c704fc88dbcfec5c2d1109e,
title = "Structural basis for glucose-6-phosphate activation of glycogen synthase",
abstract = "Regulation of the storage of glycogen, one of the major energy reserves, is of utmost metabolic importance. In eukaryotes, this regulation is accomplished through glucose-6-phosphate levels and protein phosphorylation. Glycogen synthase homologs in bacteria and archaea lack regulation, while the eukaryotic enzymes are inhibited by protein kinase mediated phosphorylation and activated by protein phosphatases and glucose-6-phosphate binding. We determined the crystal structures corresponding to the basal activity state and glucose-6-phosphate activated state of yeast glycogen synthase-2. The enzyme is assembled into an unusual tetramer by an insertion unique to the eukaryotic enzymes, and this subunit interface is rearranged by the binding of glucose-6-phosphate, which frees the active site cleft and facilitates catalysis. Using both mutagenesis and intein-mediated phospho-peptide ligation experiments, we demonstrate that the enzyme's response to glucose-6-phosphate is controlled by Arg583 and Arg587, while four additional arginine residues present within the same regulatory helix regulate the response to phosphorylation.",
keywords = "Allosteric activation, Glycosyltransferase",
author = "Sulochanadevi Baskaran and Peter Roach and {De Paoli-Roach}, Anna and Thomas Hurley",
year = "2010",
month = "10",
day = "12",
doi = "10.1073/pnas.1006340107",
language = "English",
volume = "107",
pages = "17563--17568",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "41",

}

TY - JOUR

T1 - Structural basis for glucose-6-phosphate activation of glycogen synthase

AU - Baskaran, Sulochanadevi

AU - Roach, Peter

AU - De Paoli-Roach, Anna

AU - Hurley, Thomas

PY - 2010/10/12

Y1 - 2010/10/12

N2 - Regulation of the storage of glycogen, one of the major energy reserves, is of utmost metabolic importance. In eukaryotes, this regulation is accomplished through glucose-6-phosphate levels and protein phosphorylation. Glycogen synthase homologs in bacteria and archaea lack regulation, while the eukaryotic enzymes are inhibited by protein kinase mediated phosphorylation and activated by protein phosphatases and glucose-6-phosphate binding. We determined the crystal structures corresponding to the basal activity state and glucose-6-phosphate activated state of yeast glycogen synthase-2. The enzyme is assembled into an unusual tetramer by an insertion unique to the eukaryotic enzymes, and this subunit interface is rearranged by the binding of glucose-6-phosphate, which frees the active site cleft and facilitates catalysis. Using both mutagenesis and intein-mediated phospho-peptide ligation experiments, we demonstrate that the enzyme's response to glucose-6-phosphate is controlled by Arg583 and Arg587, while four additional arginine residues present within the same regulatory helix regulate the response to phosphorylation.

AB - Regulation of the storage of glycogen, one of the major energy reserves, is of utmost metabolic importance. In eukaryotes, this regulation is accomplished through glucose-6-phosphate levels and protein phosphorylation. Glycogen synthase homologs in bacteria and archaea lack regulation, while the eukaryotic enzymes are inhibited by protein kinase mediated phosphorylation and activated by protein phosphatases and glucose-6-phosphate binding. We determined the crystal structures corresponding to the basal activity state and glucose-6-phosphate activated state of yeast glycogen synthase-2. The enzyme is assembled into an unusual tetramer by an insertion unique to the eukaryotic enzymes, and this subunit interface is rearranged by the binding of glucose-6-phosphate, which frees the active site cleft and facilitates catalysis. Using both mutagenesis and intein-mediated phospho-peptide ligation experiments, we demonstrate that the enzyme's response to glucose-6-phosphate is controlled by Arg583 and Arg587, while four additional arginine residues present within the same regulatory helix regulate the response to phosphorylation.

KW - Allosteric activation

KW - Glycosyltransferase

UR - http://www.scopus.com/inward/record.url?scp=78049302247&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049302247&partnerID=8YFLogxK

U2 - 10.1073/pnas.1006340107

DO - 10.1073/pnas.1006340107

M3 - Article

VL - 107

SP - 17563

EP - 17568

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

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

SN - 0027-8424

IS - 41

ER -