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- EMDB-13752: Human GYS1-GYG1 complex activated state bound to glucose-6-phosphate -

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Basic information

Entry
Database: EMDB / ID: EMD-13752
TitleHuman GYS1-GYG1 complex activated state bound to glucose-6-phosphate
Map dataLocally filtered map
Sample
  • Complex: Ternary complex of phosphorylated full-length human glycogen synthase 1 in complex with minimum region of human glycogenin-1
    • Protein or peptide: Glycogen [starch] synthase, muscle
    • Protein or peptide: Glycogenin-1
  • Ligand: 6-O-phosphono-alpha-D-glucopyranose
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 / 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 / glucose binding / glycogen biosynthetic process / Glycogen breakdown (glycogenolysis) / glycosyltransferase activity / inclusion body / Myoclonic epilepsy of Lafora / Glycogen synthesis / lysosomal lumen / manganese ion binding / heart development / secretory granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / protein homodimerization activity / extracellular region / membrane / cytosol / cytoplasm
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: 3.7 Å
AuthorsMcCorvie TJ / Shrestha L / Froese DS / Ferreira IM / Yue WW
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate.
Authors: Thomas J McCorvie / Paula M Loria / Meihua Tu / Seungil Han / Leela Shrestha / D Sean Froese / Igor M Ferreira / Allison P Berg / Wyatt W Yue /
Abstract: Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by ...Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by allosteric activation of glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0-4.0 Å resolution of phosphorylated human GYS1, in complex with a minimal interacting region of glycogenin, in the inhibited, activated and catalytically competent states. Phosphorylations of specific terminal residues are sensed by different arginine clusters, locking the GYS1 tetramer in an inhibited state via intersubunit interactions. The Glc6P activator promotes conformational change by disrupting these interactions and increases the flexibility of GYS1, such that it is poised to adopt a catalytically competent state when the sugar donor UDP-glucose (UDP-glc) binds. We also identify an inhibited-like conformation that has not transitioned into the activated state, in which the locking interaction of phosphorylation with the arginine cluster impedes subsequent conformational changes due to Glc6P binding. Our results address longstanding questions regarding the mechanism of human GYS1 regulation.
History
DepositionOct 17, 2021-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateJul 27, 2022-
Current statusJul 27, 2022Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_13752.png

Downloads & links

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Map

FileDownload / File: emd_13752.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocally filtered map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 300 pix.
= 325.8 Å		1.09 Å/pix.
x 300 pix.
= 325.8 Å		1.09 Å/pix.
x 300 pix.
= 325.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.086 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0281
Minimum - Maximum-0.12343154 - 0.20183153
Average (Standard dev.)0.00015981487 (±0.0045978967)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 325.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Sharpened map

Fileemd_13752_additional_1.map
AnnotationSharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Non-sharpened map

Fileemd_13752_additional_2.map
AnnotationNon-sharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map 1

Fileemd_13752_half_map_1.map
AnnotationHalf-map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map 2

Fileemd_13752_half_map_2.map
AnnotationHalf-map 2
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of phosphorylated full-length human glycogen synt...

EntireName: Ternary complex of phosphorylated full-length human glycogen synthase 1 in complex with minimum region of human glycogenin-1
Components
  • Complex: Ternary complex of phosphorylated full-length human glycogen synthase 1 in complex with minimum region of human glycogenin-1
    • 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: Ternary complex of phosphorylated full-length human glycogen synt...

SupramoleculeName: Ternary complex of phosphorylated full-length human glycogen synthase 1 in complex with minimum region of human glycogenin-1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human) / Tissue: muscle
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 350 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) / Tissue: Muscle
Molecular weightTheoretical: 83.88543 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MPLNRTLSMS SLPGLEDWED EFDLENAVLF EVAWEVANKV GGIYTVLQTK AKVTGDEWGD NYFLVGPYTE QGVRTQVELL EAPTPALKR TLDSMNSKGC KVYFGRWLIE GGPLVVLLDV GASAWALERW KGELWDTCNI GVPWYDREAN DAVLFGFLTT W FLGEFLAQ ...String:
MPLNRTLSMS SLPGLEDWED 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 YRYPRPA SV PPSPSLSRHS SPHQSEDEED PRNGPLEEDG ERYDEDEEAA KDRRNIRAPE WPRRASCTSS TSGSKRNSVD TATSSSLS T PSEPLSPTSS LGEERN

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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: 39.422621 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MTDQAFVTLT TNDAYAKGAL VLGSSLKQHR TTRRLVVLAT PQVSDSMRKV LETVFDEVIM VDVLDSGDSA HLTLMKRPEL GVTLTKLHC WSLTQYSKCV FMDADTLVLA NIDDLFDREE LSAAPDPGWP DCFNSGVFVY QPSVETYNQL LHLASEQGSF D GGDQGILN ...String:
MTDQAFVTLT TNDAYAKGAL VLGSSLKQHR TTRRLVVLAT PQVSDSMRKV LETVFDEVIM VDVLDSGDSA HLTLMKRPEL GVTLTKLHC WSLTQYSKCV FMDADTLVLA NIDDLFDREE LSAAPDPGWP DCFNSGVFVY QPSVETYNQL LHLASEQGSF D GGDQGILN TFFSSWATTD IRKHLPFIYN LSSISIYSYL PAFKVFGASA KVVHFLGRVK PWNYTYDPKT KSVKSEAHDP NM THPEFLI LWWNIFTTNV LPLLQQFGLV KDTCSYVNVL SDLVYTLAFS CGFCRKEDVS GAISHLSLGE IPAMAQPFVS SEE RKERWE QGQADYMGAD SFDNIKRKLD TYLQ

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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

Concentration0.75 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMHEPESHEPES
200.0 mMNaClSodium chloridesodium chloride
2.0 mMTCEPTCEP
0.05 % (v/v)TWEEN-20Tween-20
5.0 mMGlucose-6-phosphateGlucose 6-phosphateGlucose-6-phosphateGlucose 6-phosphate

Details: 25 mM HEPES, pH 7.5, 200 mM NaCl, 2.0 mM TCEP, 0.05% (v/v) tween-20 filtered sterilised with 5 mM glucose-6-phosphate
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 12.0 nm / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Average exposure time: 1.22 sec. / Average electron dose: 55.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4391867
CTF correctionSoftware - Name: CTFFIND (ver. 4.1)
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.1.)
Final 3D classificationSoftware - Name: RELION (ver. 3.1.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1.1.)
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1.) / Number images used: 15379
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

3nb0

chain_id: A, residue_range: 22-659

4qlb

chain_id: E, residue_range: 268-301
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 116.12 / Target criteria: correlation coefficient
Output model

PDB-7q12:
Human GYS1-GYG1 complex activated state bound to glucose-6-phosphate

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