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- PDB-8cvy: Human glycogenin-1 and glycogen synthase-1 complex in the apo mob... -

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Basic information

Entry
Database: PDB / ID: 8cvy
TitleHuman glycogenin-1 and glycogen synthase-1 complex in the apo mobile state
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
Glycogen [starch] synthase, muscle / Glycogenin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 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
C: Glycogen [starch] synthase, muscle
G: Glycogenin-1
D: Glycogen [starch] synthase, muscle
H: Glycogenin-1
B: Glycogen [starch] synthase, muscle


Theoretical massNumber of molelcules
Total (without water)409,2207
Polymers409,2207
Non-polymers00
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
21C
12I
22E
13I
23G
14J
24D
15J
25F
16C
26E
17C
27G
18D
28F
19E
29G

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010I22 - 626
2010C22 - 626
1020I22 - 626
2020E22 - 626
1030I292 - 600
2030G292 - 600
1040J299 - 330
2040D299 - 330
1050J299 - 330
2050F299 - 330
1060C22 - 626
2060E22 - 626
1070C292 - 600
2070G292 - 600
1080D299 - 332
2080F299 - 332
1090E292 - 600
2090G292 - 600

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

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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.: 3 / 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

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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 apo ordered state
Type: COMPLEX / Entity ID: all / 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
SpecimenConc.: 0.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: 7 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: 2400 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: 8536

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Processing

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
EM software
IDNameVersionCategory
1cryoSPARCv3.3.2particle selection
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: 914196
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 184341 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: RECIPROCAL
RefinementResolution: 3.6→296.2 Å / Cor.coef. Fo:Fc: 0.613 / SU B: 26.511 / SU ML: 0.333 / ESU R: 0.211
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.45866 --
obs0.45866 1166282 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 114.366 Å2
Baniso -1Baniso -2Baniso -3
1-1.4 Å20.23 Å2-0.3 Å2
2--2.16 Å20.47 Å2
3----3.56 Å2
Refinement stepCycle: 1 / Total: 17921
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.01218388
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg1.2371.63424923
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.72152219
ELECTRON MICROSCOPYr_dihedral_angle_2_deg25.94121.3011061
ELECTRON MICROSCOPYr_dihedral_angle_3_deg17.567153000
ELECTRON MICROSCOPYr_dihedral_angle_4_deg11.06515144
ELECTRON MICROSCOPYr_chiral_restr0.1130.22305
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.0214228
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_it5.78110.838897
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it10.66116.20811109
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it5.80411.9959491
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined29.33277041
ELECTRON MICROSCOPYr_long_range_B_other
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.6→3.694 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.794 86062 -
obs--100 %

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