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Structural Basis For The Recruitment Of Glycogen Synthase By Glycogenin

E. Zeqiraj, X. Tang, R. W. Hunter, M. García-Rocha, A. Judd, M. Deák, Alexander von Wilamowitz-Moellendorff, I. Kurinov, J. Guinovart, M. Tyers, K. Sakamoto, F. Sicheri
Published 2014 · Biology, Medicine

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Significance The body stores excess blood glucose as glycogen, a sugary substance that contains up to 55,000 glucose molecules joined together as a chain, mostly in liver and muscle cells. Conversion of glucose to glycogen and glycogen to glucose in these cells plays an important role in regulating blood glucose levels. Glycogen ensures that we don’t run out of fuel during prolonged exercise. To make glycogen from blood sugar, cells need two enzymes: glycogenin and glycogen synthase. Glycogenin kick starts the process by first linking to itself a string of glucose residues and then recruiting glycogen synthase to elaborate this “seed” glycogen particle. Here, we describe the molecular details of how these two enzymes come together and begin to make glycogen. Glycogen is a primary form of energy storage in eukaryotes that is essential for glucose homeostasis. The glycogen polymer is synthesized from glucose through the cooperative action of glycogen synthase (GS), glycogenin (GN), and glycogen branching enzyme and forms particles that range in size from 10 to 290 nm. GS is regulated by allosteric activation upon glucose-6-phosphate binding and inactivation by phosphorylation on its N- and C-terminal regulatory tails. GS alone is incapable of starting synthesis of a glycogen particle de novo, but instead it extends preexisting chains initiated by glycogenin. The molecular determinants by which GS recognizes self-glucosylated GN, the first step in glycogenesis, are unknown. We describe the crystal structure of Caenorhabditis elegans GS in complex with a minimal GS targeting sequence in GN and show that a 34-residue region of GN binds to a conserved surface on GS that is distinct from previously characterized allosteric and binding surfaces on the enzyme. The interaction identified in the GS-GN costructure is required for GS–GN interaction and for glycogen synthesis in a cell-free system and in intact cells. The interaction of full-length GS-GN proteins is enhanced by an avidity effect imparted by a dimeric state of GN and a tetrameric state of GS. Finally, the structure of the N- and C-terminal regulatory tails of GS provide a basis for understanding phosphoregulation of glycogen synthesis. These results uncover a central molecular mechanism that governs glycogen metabolism.
This paper references
10.1016/j.ijbiomac.2009.08.006
Comparative structural analyses of purified glycogen particles from rat liver, human skeletal muscle and commercial preparations.
Je-Hoon Ryu (2009)
10.1074/jbc.M808576200
Control of Liver Glycogen Synthase Activity and Intracellular Distribution by Phosphorylation*
S. Ros (2009)
10.1038/sj.emboj.7600324
Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation
A. Buschiazzo (2004)
10.1107/S0907444909007835
ALINE: a WYSIWYG protein-sequence alignment editor for publication-quality alignments.
C. Bond (2009)
10.2337/db10-1148
Molecular Mechanism by Which AMP-Activated Protein Kinase Activation Promotes Glycogen Accumulation in Muscle
R. W. Hunter (2011)
10.1042/BJ20111416
Glycogen and its metabolism: some new developments and old themes.
P. Roach (2012)
10.1016/j.cmet.2012.11.010
Linking glycogen and senescence in cancer cells.
S. Ros (2012)
Cellular mechanism of insulin resistance in skeletal muscle.
K. Petersen (2002)
10.1107/S0021889807021206
Phaser crystallographic software
A. McCoy (2007)
10.2337/db13-0880
Glucose-6-Phosphate–Mediated Activation of Liver Glycogen Synthase Plays a Key Role in Hepatic Glycogen Synthesis
Alexander von Wilamowitz-Moellendorff (2013)
10.1056/NEJMoa0900661
Glycogenin-1 deficiency and inactivated priming of glycogen synthesis.
A. Moslemi (2010)
10.1107/S0907444994003112
The CCP4 suite: programs for protein crystallography.
Collaborative Computational (1994)
10.1111/J.1432-1033.1988.TB14294.X
Glycogenin is the priming glucosyltransferase required for the initiation of glycogen biogenesis in rabbit skeletal muscle.
J. Pitcher (1988)
, Steiner R REFMAC 5 for the Refinement of Macromolecular Crystal Structures
PD Adams (2002)
GYG 2
A Buschiazzo (2004)
10.1093/NAR/GKH340
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
R. Edgar (2004)
Rabbit skeletal muscle glycogen synthase expressed in COS cells. Identification of regulatory phosphorylation sites.
A. V. Skurat (1994)
10.1016/S0378-1119(99)00520-X
Structure and chromosomal localization of the human glycogenin-2 gene GYG2.
L. Zhai (2000)
10.1073/pnas.1113921108
Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis
A. Chaikuad (2011)
10.1107/S0907444904019158
Coot: model-building tools for molecular graphics.
P. Emsley (2004)
10.1002/BIP.360221211
Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features
W. Kabsch (1983)
10.1074/jbc.M111.287813
Mechanisms of Monomeric and Dimeric Glycogenin Autoglucosylation*
F. Issoglio (2011)
10.1016/S0022-2836(02)00305-4
Crystal structure of the autocatalytic initiator of glycogen biosynthesis, glycogenin.
B. Gibbons (2002)
10.1146/annurev.biochem.76.061005.092322
Glycosyltransferases: structures, functions, and mechanisms.
L. Lairson (2008)
10.2174/1566524024605761
Glycogen and its metabolism.
P. Roach (2002)
10.1111/J.1432-1033.1987.TB13637.X
Identification of the 38-kDa subunit of rabbit skeletal muscle glycogen synthase as glycogenin.
J. Pitcher (1987)
10.1002/emmm.201100174
Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease
J. Valles-Ortega (2011)
10.1016/J.ABB.2006.09.024
Interaction between glycogenin and glycogen synthase.
A. V. Skurat (2006)
10.1038/nprot.2007.135
A protocol for rapid generation of recombinant adenoviruses using the AdEasy system
Jinyong Luo (2007)
10.1038/jcbfm.2014.33
Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia
Isabel Saez (2014)
10.1111/febs.12059
Regulation of glycogen synthase from mammalian skeletal muscle – a unifying view of allosteric and covalent regulation
Daniel C. Palm (2013)
, Steiner R REFMAC 5 for the Refinement of Macromolecular Crystal Structures
PD Adams (2002)
10.1016/j.cmet.2010.10.006
Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle.
M. Bouskila (2010)
10.1152/JAPPLPHYSIOL.00585.2001
Quantification of subcellular glycogen in resting human muscle: granule size, number, and location.
I. Marchand (2002)
10.1107/S0907444909047337
XDS
W. Kabsch (2010)
Lebedev A , Pannu N , Steiner R REFMAC 5 for the Refinement of Macromolecular Crystal Structures
PD Adams (2002)
10.1016/J.BBRC.2007.08.080
AMP-activated protein kinase does not associate with glycogen α-particles from rat liver
G. Parker (2007)
10.1073/pnas.1006340107
Structural basis for glucose-6-phosphate activation of glycogen synthase
Sulochanadevi Baskaran (2010)
10.1107/S0907444911001314
REFMAC5 for the refinement of macromolecular crystal structures
G. Murshudov (2011)
10.1107/S0907444902016657
PHENIX: building new software for automated crystallographic structure determination.
P. Adams (2002)



This paper is referenced by
10.7912/C23K6H
Structural basis for regulated inhibition and substrate selection in yeast glycogen synthase
K. Mahalingan (2016)
SSIEM 2015
Wyatt W. Yue (2016)
10.1016/j.cmet.2017.06.008
Lack of Glycogenin Causes Glycogen Accumulation and Muscle Function Impairment.
Giorgia Testoni (2017)
10.1101/752121
Genomics reveals the origins of ancient specimens
Q. Cong (2019)
10.1101/764241
A glycogenin homolog controls Toxoplasma gondii growth via glycosylation of an E3 ubiquitin ligase
Msano Mandalasi (2020)
10.1016/j.sbi.2016.07.007
The conformational plasticity of glycosyltransferases.
D. Albesa-Jové (2016)
10.7912/C22939
Glycogen metabolism in Lafora disease
Christopher J. Contreras (2017)
10.1074/jbc.RA120.013792
A terminal α3-galactose modification regulates an E3 ubiquitin ligase subunit in Toxoplasma gondii
Msano Mandalasi (2020)
10.1016/j.bbagrm.2018.04.002
BmSUC1 is essential for glycometabolism modulation in the silkworm, Bombyx mori.
Quan Gan (2018)
10.1016/j.sbi.2014.08.012
Advances in understanding glycosyltransferases from a structural perspective
T. Gloster (2014)
10.1093/database/baz114
Representing glycophenotypes: semantic unification of glycobiology resources for disease discovery
Jean-Philippe Gourdine (2019)
10.1042/BCJ20190441
From the seminal discovery of proteoglycogen and glycogenin to emerging knowledge and research on glycogen biology.
J. Curtino (2019)
A novel role for glycogenin in the regulation of glycogen metabolism
Giorgia Testoni (2016)
Evaluating the Glycogenic Activity and Therapeutic Capacity of PPP1R3D in a Mouse Model of Lafora Disease
L. Israelian (2018)
10.3390/ijms21197011
A Review of Starch Biosynthesis in Relation to the Building Block-Backbone Model
I. Tetlow (2020)
10.1021/acsomega.7b00922
On the Role of Catabolic Enzymes in Biosynthetic Models of Glycogen Molecular Weight Distributions
Sharif S. Nada (2017)
10.1016/j.carbpol.2020.116181
Characterization of glycogen molecular structure in the worm Caenorhabditis elegans.
Qing-hua Liu (2020)
10.1007/978-3-030-27480-1_3
Structure and Regulation of Glycogen Synthase in the Brain.
B. Pederson (2019)
10.1021/acs.biochem.6b00884
Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation.
K. Mahalingan (2017)
10.1007/978-3-030-27480-1_2
Brain Glycogen Structure and Its Associated Proteins: Past, Present and Future.
M. K. Brewer (2019)
Identification of Therapeutic Targets in a Glycogen Storage Disease Type IV Mouse Model
Erin E Chown (2018)
10.1016/j.mam.2015.08.004
Getting a handle on glycogen synthase - Its interaction with glycogenin.
E. Zeqiraj (2015)
10.1007/s10545-016-9923-3
From structural biology to designing therapy for inborn errors of metabolism
W. Yue (2016)
10.1016/j.bbagen.2016.08.021
A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.
C. A. Maile (2017)
10.1074/jbc.M116.773408
Mechanistic insights into the allosteric regulation of bacterial ADP-glucose pyrophosphorylases
Natalia Comino (2017)
10.1007/978-3-7091-1830-6
Functional Ultrastructure
M. Pavelka (2015)
10.1074/jbc.RA118.005634
Myocardial-specific ablation of Jumonji and AT-rich interaction domain–containing 2 (Jarid2) leads to dilated cardiomyopathy in mice
Eunjin Cho (2019)
10.1042/BCJ20170558
Structural basis of glycogen metabolism in bacteria.
J. O. Cifuente (2019)
10.1016/j.pep.2014.12.007
Expression and purification of functional human glycogen synthase-1:glycogenin-1 complex in insect cells
R. W. Hunter (2015)
10.1074/jbc.M116.770446
Defining the enzymatic pathway for polymorphic O-glycosylation of the pneumococcal serine-rich repeat protein PsrP
Y. Jiang (2017)
10.1093/glycob/cww086
Biological roles of glycans
A. Varki (2017)
10.1039/c5cs00600g
Glycosyltransferases: mechanisms and applications in natural product development.
D. Liang (2015)
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