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- EMDB-30599: Cryo-EM structures of human GMPPA/GMPPB complex bound to GDP-Mannose -

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Basic information

Entry
Database: EMDB / ID: EMD-30599
TitleCryo-EM structures of human GMPPA/GMPPB complex bound to GDP-Mannose
Map data
Sample
  • Complex: GMPPA/GMPPB complex
    • Protein or peptide: Mannose-1-phosphate guanyltransferase beta
    • Protein or peptide: Mannose-1-phosphate guanyltransferase alpha
  • Ligand: GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE
  • Ligand: MAGNESIUM ION
  • Ligand: water
KeywordsGMPPA / GMPPB / gdp-mannose homeostasis / CELL CYCLE / TRANSFERASE
Function / homology
Function and homology information


negative regulation of nucleobase-containing compound metabolic process / GDP-mannose pyrophosphorylase complex / negative regulation of small molecule metabolic process / negative regulation of phosphate metabolic process / mannose-1-phosphate guanylyltransferase / negative regulation of biosynthetic process / mannose-1-phosphate guanylyltransferase (GTP) activity / GDP-mannose biosynthetic process from mannose / skeletal muscle organ development / Synthesis of GDP-mannose ...negative regulation of nucleobase-containing compound metabolic process / GDP-mannose pyrophosphorylase complex / negative regulation of small molecule metabolic process / negative regulation of phosphate metabolic process / mannose-1-phosphate guanylyltransferase / negative regulation of biosynthetic process / mannose-1-phosphate guanylyltransferase (GTP) activity / GDP-mannose biosynthetic process from mannose / skeletal muscle organ development / Synthesis of GDP-mannose / GDP-mannose metabolic process / muscle organ morphogenesis / molecular sensor activity / GDP-mannose biosynthetic process / telencephalon development / neuromuscular process / : / motor behavior / enzyme inhibitor activity / cognition / transferase activity / neuron apoptotic process / GTP binding / enzyme binding / extracellular exosome / metal ion binding / cytoplasm / cytosol
Similarity search - Function
Mannose-1-phosphate guanyltransferase, N-terminal domain / : / GMPPB C-terminal domain / : / Hexapeptide transferase, conserved site / Hexapeptide-repeat containing-transferases signature. / Nucleotidyl transferase domain / Nucleotidyl transferase / Nucleotide-diphospho-sugar transferases
Similarity search - Domain/homology
Mannose-1-phosphate guanylyltransferase regulatory subunit alpha / Mannose-1-phosphate guanylyltransferase catalytic subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / negative staining / Resolution: 3.4 Å
AuthorsZheng L / Liu Z
Funding support1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis.
Authors: Lvqin Zheng / Zhe Liu / Yan Wang / Fan Yang / Jinrui Wang / Wenjie Huang / Jiao Qin / Min Tian / Xiaotang Cai / Xiaohui Liu / Xianming Mo / Ning Gao / Da Jia /
Abstract: GDP-mannose (GDP-Man) is a key metabolite essential for protein glycosylation and glycophosphatidylinositol anchor synthesis, and aberrant cellular GDP-Man levels have been associated with multiple ...GDP-mannose (GDP-Man) is a key metabolite essential for protein glycosylation and glycophosphatidylinositol anchor synthesis, and aberrant cellular GDP-Man levels have been associated with multiple human diseases. How cells maintain homeostasis of GDP-Man is unknown. Here, we report the cryo-EM structures of human GMPPA-GMPPB complex, the protein machinery responsible for GDP-Man synthesis, in complex with GDP-Man or GTP. Unexpectedly, we find that the catalytically inactive subunit GMPPA displays a much higher affinity to GDP-Man than the active subunit GMPPB and, subsequently, inhibits the catalytic activity of GMPPB through a unique C-terminal loop of GMPPA. Importantly, disruption of the interactions between GMPPA and GMPPB or the binding of GDP-Man to GMPPA in zebrafish leads to abnormal brain development and muscle abnormality, analogous to phenotypes observed in individuals carrying GMPPA or GMPPB mutations. We conclude that GMPPA acts as a cellular sensor to maintain mannose homeostasis through allosterically regulating GMPPB.
History
DepositionOct 2, 2020-
Header (metadata) releaseMay 5, 2021-
Map releaseMay 5, 2021-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.02
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  • Surface view with fitted model
  • Atomic models: PDB-7d72
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30599.png

Downloads & links

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Map

FileDownload / File: emd_30599.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 240 pix.
= 253.68 Å		1.06 Å/pix.
x 240 pix.
= 253.68 Å		1.06 Å/pix.
x 240 pix.
= 253.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.057 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.0767847 - 0.13578337
Average (Standard dev.)0.000008423979 (±0.0055936086)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 253.68001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0571.0571.057
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z253.680253.680253.680
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0770.1360.000

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Supplemental data

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Sample components

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Entire : GMPPA/GMPPB complex

EntireName: GMPPA/GMPPB complex
Components
  • Complex: GMPPA/GMPPB complex
    • Protein or peptide: Mannose-1-phosphate guanyltransferase beta
    • Protein or peptide: Mannose-1-phosphate guanyltransferase alpha
  • Ligand: GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE
  • Ligand: MAGNESIUM ION
  • Ligand: water

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Supramolecule #1: GMPPA/GMPPB complex

SupramoleculeName: GMPPA/GMPPB complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mannose-1-phosphate guanyltransferase beta

MacromoleculeName: Mannose-1-phosphate guanyltransferase beta / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO / EC number: mannose-1-phosphate guanylyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.878316 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MKALILVGGY GTRLRPLTLS TPKPLVDFCN KPILLHQVEA LAAAGVDHVI LAVSYMSQVL EKEMKAQEQR LGIRISMSHE EEPLGTAGP LALARDLLSE TADPFFVLNS DVICDFPFQA MVQFHRHHGQ EGSILVTKVE EPSKYGVVVC EADTGRIHRF V EKPQVFVS ...String:
MKALILVGGY GTRLRPLTLS TPKPLVDFCN KPILLHQVEA LAAAGVDHVI LAVSYMSQVL EKEMKAQEQR LGIRISMSHE EEPLGTAGP LALARDLLSE TADPFFVLNS DVICDFPFQA MVQFHRHHGQ EGSILVTKVE EPSKYGVVVC EADTGRIHRF V EKPQVFVS NKINAGMYIL SPAVLQRIQL QPTSIEKEVF PIMAKEGQLY AMELQGFWMD IGQPKDFLTG MCLFLQSLRQ KQ PERLCSG PGIVGNVLVD PSARIGQNCS IGPNVSLGPG VVVEDGVCIR RCTVLRDARI RSHSWLESCI VGWRCRVGQW VRM ENVTVL GEDVIVNDEL YLNGASVLPH KSIGESVPEP RIIM

UniProtKB: Mannose-1-phosphate guanylyltransferase catalytic subunit beta

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Macromolecule #2: Mannose-1-phosphate guanyltransferase alpha

MacromoleculeName: Mannose-1-phosphate guanyltransferase alpha / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.341961 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MLKAVILIGG PQKGTRFRPL SFEVPKPLFP VAGVPMIQHH IEACAQVPGM QEILLIGFYQ PDEPLTQFLE AAQQEFNLPV RYLQEFAPL GTGGGLYHFR DQILAGSPEA FFVLNADVCS DFPLSAMLEA HRRQRHPFLL LGTTANRTQS LNYGCIVENP Q THEVLHYV ...String:
MLKAVILIGG PQKGTRFRPL SFEVPKPLFP VAGVPMIQHH IEACAQVPGM QEILLIGFYQ PDEPLTQFLE AAQQEFNLPV RYLQEFAPL GTGGGLYHFR DQILAGSPEA FFVLNADVCS DFPLSAMLEA HRRQRHPFLL LGTTANRTQS LNYGCIVENP Q THEVLHYV EKPSTFISDI INCGIYLFSP EALKPLRDVF QRNQQDGQLE DSPGLWPGAG TIRLEQDVFS ALAGQGQIYV HL TDGIWSQ IKSAGSALYA SRLYLSRYQD THPERLAKHT PGGPWIRGNV YIHPTAKVAP SAVLGPNVSI GKGVTVGEGV RLR ESIVLH GATLQEHTCV LHSIVGWGST VGRWARVEGT PSDPNPNDPR ARMDSESLFK DGKLLPAITI LGCRVRIPAE VLIL NSIVL PHKELSRSFT NQIIL

UniProtKB: Mannose-1-phosphate guanylyltransferase regulatory subunit alpha

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Macromolecule #3: GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE / type: ligand / ID: 3 / Number of copies: 12 / Formula: GDD
Molecular weightTheoretical: 605.341 Da
Chemical component information

ChemComp-GDD:
GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 6 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodnegative staining, cryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 8
StainingType: NEGATIVE / Material: Uranyl Acetate
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DARK FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 57299
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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