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- PDB-8cvx: Human glycogenin-1 and glycogen synthase-1 complex in the presenc... -

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Basic information

Entry
Database: PDB / ID: 8cvx
TitleHuman glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
Components
  • Glycogen [starch] synthase, muscle
  • Glycogenin-1
KeywordsTRANSFERASE / Metabolism Glycogen synthesis / Glycogen synthase Glycogenin
Function / homology
Function and homology information


glycogen synthase activity, transferring glucose-1-phosphate / Glycogen storage disease type XV (GYG1) / Glycogen storage disease type 0 (muscle GYS1) / glycogen(starch) synthase / Glycogen storage disease type II (GAA) / glycogenin glucosyltransferase / glycogenin glucosyltransferase activity / : / glycogen (starch) synthase activity / D-glucose binding ...glycogen synthase activity, transferring glucose-1-phosphate / Glycogen storage disease type XV (GYG1) / Glycogen storage disease type 0 (muscle GYS1) / glycogen(starch) synthase / Glycogen storage disease type II (GAA) / glycogenin glucosyltransferase / glycogenin glucosyltransferase activity / : / glycogen (starch) synthase activity / D-glucose binding / glycogen biosynthetic process / Glycogen breakdown (glycogenolysis) / glycosyltransferase activity / inclusion body / Myoclonic epilepsy of Lafora / Glycogen synthesis / lysosomal lumen / heart development / manganese ion binding / secretory granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / protein homodimerization activity / extracellular region / membrane / cytoplasm / cytosol
Similarity search - Function
Glycogen synthase / Glycogen synthase / Glycosyl transferase, family 8 / Glycosyl transferase family 8 / Nucleotide-diphospho-sugar transferases
Similarity search - Domain/homology
6-O-phosphono-alpha-D-glucopyranose / Glycogen [starch] synthase, muscle / Glycogenin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLiu, Y. / Fastman, N.M. / Tzitzilonis, C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Cell Rep / Year: 2022
Title: The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex.
Authors: Nathan M Fastman / Yuxi Liu / Vyas Ramanan / Hanne Merritt / Eileen Ambing / Anna A DePaoli-Roach / Peter J Roach / Thomas D Hurley / Kevin T Mellem / Julie C Ullman / Eric Green / David ...Authors: Nathan M Fastman / Yuxi Liu / Vyas Ramanan / Hanne Merritt / Eileen Ambing / Anna A DePaoli-Roach / Peter J Roach / Thomas D Hurley / Kevin T Mellem / Julie C Ullman / Eric Green / David Morgans / Christos Tzitzilonis /
Abstract: Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes ...Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes glycogenin-1 (GYG1), which seeds the molecule by autoglucosylation, and glycogen synthase-1 (GYS1), which extends the glycogen chain. Although both enzymes are required for proper glycogen production, the nature of their interaction has been enigmatic. Here, we present the human GYS1:GYG1 complex in multiple conformations representing different functional states. We observe an asymmetric conformation of GYS1 that exposes an interface for close GYG1 association, and propose this state facilitates handoff of the GYG1-associated glycogen chain to a GYS1 subunit for elongation. Full activation of GYS1 widens the GYG1-binding groove, enabling GYG1 release concomitant with glycogen chain growth. This structural mechanism connecting chain nucleation and extension explains the apparent stepwise nature of glycogen synthesis and suggests distinct states to target for GSD-modifying therapeutics.
History
DepositionMay 18, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 14, 2022Group: Data processing / Category: em_3d_reconstruction / Item: _em_3d_reconstruction.resolution
Revision 1.3Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glycogen [starch] synthase, muscle
E: Glycogenin-1
H: Glycogenin-1
G: Glycogenin-1
F: Glycogenin-1
B: Glycogen [starch] synthase, muscle
D: Glycogen [starch] synthase, muscle
C: Glycogen [starch] synthase, muscle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)449,82112
Polymers448,7818
Non-polymers1,0414
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11I
21G
12I
22E
13I
23C
14J
24F
15J
25D
16J
26H
17F
27D
18F
28H
19D
29H
110G
210E
111G
211C
112E
212C

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010I24 - 625
2010G24 - 625
1020I24 - 625
2020E24 - 625
1030I24 - 625
2030C24 - 625
1040J301 - 333
2040F301 - 333
1050J301 - 331
2050D301 - 331
1060J301 - 333
2060H301 - 333
1070F301 - 331
2070D301 - 331
1080F301 - 333
2080H301 - 333
1090D301 - 331
2090H301 - 331
10100G24 - 625
20100E24 - 625
10110G24 - 625
20110C24 - 625
10120E24 - 625
20120C24 - 625

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12

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Components

#1: Protein
Glycogen [starch] synthase, muscle


Mass: 72634.438 Da / Num. of mol.: 4 / Mutation: S8E,S11E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GYS1, GYS / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P13807, glycogen(starch) synthase
#2: Protein
Glycogenin-1 / GN-1 / GN1


Mass: 39560.789 Da / Num. of mol.: 4 / Mutation: Y195F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GYG1, GYG / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P46976, glycogenin glucosyltransferase
#3: Sugar
ChemComp-G6P / 6-O-phosphono-alpha-D-glucopyranose / ALPHA-D-GLUCOSE-6-PHOSPHATE / 6-O-phosphono-alpha-D-glucose / 6-O-phosphono-D-glucose / 6-O-phosphono-glucose


Type: D-saccharide, alpha linking / Mass: 260.136 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H13O9P / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
a-D-Glcp6PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.45 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9 / Plasmid: pFastBac
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMTrisC4H11NO31
2150 mMsodium chlorideNaCl1
31 mMTCEPC9H15O6P1
40.0005 w/vbeta-octyl glucosideC14H28O61
52 mMglucose-6-phosphateC6H13O9P1
SpecimenConc.: 0.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: 9 sec blotting time, 15 blot force

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of real images: 6797

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Processing

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4cryoSPARCv3.3.2CTF correction
7MOLREPmodel fitting
9REFMACmodel refinement
10cryoSPARCv3.3.2initial Euler assignment
11cryoSPARCv3.3.2final Euler assignment
12cryoSPARCv3.3.2classification
13cryoSPARCv3.3.23D reconstruction
CTF correctionDetails: CTF correction was performed in batch in early steps. CTF correction was performed on per particle bases in the last iterations
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1383196
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 451737 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: RECIPROCAL
RefinementResolution: 3.5→155.41 Å / Cor.coef. Fo:Fc: 0.567 / SU B: 58.693 / SU ML: 0.819 / ESU R: 0.939
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.4662 --
obs0.4662 143928 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 83.503 Å2
Baniso -1Baniso -2Baniso -3
1--1.51 Å2-1.83 Å2-2.63 Å2
2---0.85 Å23.61 Å2
3---2.36 Å2
Refinement stepCycle: 1 / Total: 20512
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0040.01221048
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg1.1011.63928537
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.07252531
ELECTRON MICROSCOPYr_dihedral_angle_2_deg32.69721.4171193
ELECTRON MICROSCOPYr_dihedral_angle_3_deg18.588153445
ELECTRON MICROSCOPYr_dihedral_angle_4_deg10.60615157
ELECTRON MICROSCOPYr_chiral_restr0.0970.22643
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.0216213
ELECTRON MICROSCOPYr_gen_planes_other
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it1.4218.39810148
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it2.69412.57212671
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it0.6658.40810900
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined13.74884431
ELECTRON MICROSCOPYr_long_range_B_other
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.5→3.591 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.12 10679 -
obs--100 %

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