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- EMDB-27020: Human glycogenin-1 and glycogen synthase-1 complex in the presenc... -

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Basic information

Entry
Database: EMDB / ID: EMD-27020
TitleHuman glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
Map dataSharpened map of GYS1:GYG1 complex in the presence of G6P
Sample
  • Complex: Human glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
    • Protein or peptide: Glycogen [starch] synthase, muscle
    • Protein or peptide: Glycogenin-1
  • Ligand: 6-O-phosphono-alpha-D-glucopyranose
KeywordsMetabolism Glycogen synthesis / Glycogen synthase Glycogenin / TRANSFERASE
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 / UDP-alpha-D-glucose:glucosyl-glycogenin alpha-D-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 / UDP-alpha-D-glucose:glucosyl-glycogenin alpha-D-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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLiu Y / Fastman NM / Tzitzilonis C
Funding support United States, 1 items
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, 2022-
Header (metadata) releaseJul 13, 2022-
Map releaseJul 13, 2022-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27020.png

Downloads & links

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Map

FileDownload / File: emd_27020.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of GYS1:GYG1 complex in the presence of G6P
Voxel sizeX=Y=Z: 0.9142 Å
Density
Contour LevelBy AUTHOR: 0.65
Minimum - Maximum-9.209706000000001 - 10.577280999999999
Average (Standard dev.)0.0003063306 (±0.21067892)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 296.2008 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27020_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened of GYS1:GYG1 complex in the presence of G6P

Fileemd_27020_additional_1.map
AnnotationUnsharpened of GYS1:GYG1 complex in the presence of G6P
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A of GYS1:GYG1 complex in the presence of G6P

Fileemd_27020_half_map_1.map
AnnotationHalf map A of GYS1:GYG1 complex in the presence of G6P
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B of GYS1:GYG1 complex in the presence of G6P

Fileemd_27020_half_map_2.map
AnnotationHalf map B of GYS1:GYG1 complex in the presence of G6P
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human glycogenin-1 and glycogen synthase-1 complex in the presenc...

EntireName: Human glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
Components
  • Complex: Human glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
    • Protein or peptide: Glycogen [starch] synthase, muscle
    • Protein or peptide: Glycogenin-1
  • Ligand: 6-O-phosphono-alpha-D-glucopyranose

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Supramolecule #1: Human glycogenin-1 and glycogen synthase-1 complex in the presenc...

SupramoleculeName: Human glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 450 KDa

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Macromolecule #1: Glycogen [starch] synthase, muscle

MacromoleculeName: Glycogen [starch] synthase, muscle / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: glycogen(starch) synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.634438 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MPLNRTLEMS ELPGLEDWED EFDLENAVLF EVAWEVANKV GGIYTVLQTK AKVTGDEWGD NYFLVGPYTE QGVRTQVELL EAPTPALKR TLDSMNSKGC KVYFGRWLIE GGPLVVLLDV GASAWALERW KGELWDTCNI GVPWYDREAN DAVLFGFLTT W FLGEFLAQ ...String:
MPLNRTLEMS ELPGLEDWED EFDLENAVLF EVAWEVANKV GGIYTVLQTK AKVTGDEWGD NYFLVGPYTE QGVRTQVELL EAPTPALKR TLDSMNSKGC KVYFGRWLIE GGPLVVLLDV GASAWALERW KGELWDTCNI GVPWYDREAN DAVLFGFLTT W FLGEFLAQ SEEKPHVVAH FHEWLAGVGL CLCRARRLPV ATIFTTHATL LGRYLCAGAV DFYNNLENFN VDKEAGERQI YH RYCMERA AAHCAHVFTT VSQITAIEAQ HLLKRKPDIV TPNGLNVKKF SAMHEFQNLH AQSKARIQEF VRGHFYGHLD FNL DKTLYF FIAGRYEFSN KGADVFLEAL ARLNYLLRVN GSEQTVVAFF IMPARTNNFN VETLKGQAVR KQLWDTANTV KEKF GRKLY ESLLVGSLPD MNKMLDKEDF TMMKRAIFAT QRQSFPPVCT HNMLDDSSDP ILTTIRRIGL FNSSADRVKV IFHPE FLSS TSPLLPVDYE EFVRGCHLGV FPSYYEPWGY TPAECTVMGI PSISTNLSGF GCFMEEHIAD PSAYGIYILD RRFRSL DDS CSQLTSFLYS FCQQSRRQRI IQRNRTERLS DLLDWKYLGR YYMSARHMAL SKAFPEHFTY EPNEADAAQG Y

UniProtKB: Glycogen [starch] synthase, muscle

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Macromolecule #2: Glycogenin-1

MacromoleculeName: Glycogenin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO / EC number: glycogenin glucosyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.560789 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPMTDQAFVT LTTNDAYAKG ALVLGSSLKQ HRTTRRLVVL ATPQVSDSMR KVLETVFDEV IMVDVLDSGD SAHLTLMKRP ELGVTLTKL HCWSLTQYSK CVFMDADTLV LANIDDLFDR EELSAAPDPG WPDCFNSGVF VYQPSVETYN QLLHLASEQG S FDGGDQGI ...String:
GPMTDQAFVT LTTNDAYAKG ALVLGSSLKQ HRTTRRLVVL ATPQVSDSMR KVLETVFDEV IMVDVLDSGD SAHLTLMKRP ELGVTLTKL HCWSLTQYSK CVFMDADTLV LANIDDLFDR EELSAAPDPG WPDCFNSGVF VYQPSVETYN QLLHLASEQG S FDGGDQGI LNTFFSSWAT TDIRKHLPFI YNLSSISIFS YLPAFKVFGA SAKVVHFLGR VKPWNYTYDP KTKSVKSEAH DP NMTHPEF LILWWNIFTT NVLPLLQQFG LVKDTCSYVN VLSDLVYTLA FSCGFCRKED VSGAISHLSL GEIPAMAQPF VSS EERKER WEQGQADYMG ADSFDNIKRK LDTYLQ

UniProtKB: Glycogenin-1

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Macromolecule #3: 6-O-phosphono-alpha-D-glucopyranose

MacromoleculeName: 6-O-phosphono-alpha-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: G6P
Molecular weightTheoretical: 260.136 Da
Chemical component information

ChemComp-G6P:
6-O-phosphono-alpha-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.9 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
25.0 mMC4H11NO3Tris
150.0 mMNaClsodium chloride
1.0 mMC9H15O6PTCEP
0.0005 w/vC14H28O6beta-octyl glucoside
2.0 mMC6H13O9Pglucose-6-phosphate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 9 sec blotting time, 15 blot force.

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 6797 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Sample stageCooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 1383196
Startup modelType of model: OTHER
Details: Prior cryo-EM maps of the same sample in slightly different conditions
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v3.3.2) / Number images used: 451737
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v3.3.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v3.3.2)
Final 3D classificationSoftware - Name: cryoSPARC (ver. v3.3.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: FLEXIBLE FIT
Output model

PDB-8cvx:
Human glycogenin-1 and glycogen synthase-1 complex in the presence of glucose-6-phosphate

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