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- PDB-7d73: Cryo-EM structure of GMPPA/GMPPB complex bound to GTP (State I) -

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Basic information

Entry
Database: PDB / ID: 7d73
TitleCryo-EM structure of GMPPA/GMPPB complex bound to GTP (State I)
Components
  • Mannose-1-phosphate guanyltransferase alpha
  • Mannose-1-phosphate guanyltransferase beta
KeywordsTRANSFERASE / GMPPA / GMPPB / GDP-Mannose homeostasis / CELL CYCLE
Function / homology
Function and homology information


GDP-mannose pyrophosphorylase complex / mannose-1-phosphate guanylyltransferase / mannose-1-phosphate guanylyltransferase (GTP) activity / GDP-mannose metabolic process / Synthesis of GDP-mannose / GDP-mannose biosynthetic process / enzyme inhibitor activity / biosynthetic process / protein glycosylation / transferase activity ...GDP-mannose pyrophosphorylase complex / mannose-1-phosphate guanylyltransferase / mannose-1-phosphate guanylyltransferase (GTP) activity / GDP-mannose metabolic process / Synthesis of GDP-mannose / GDP-mannose biosynthetic process / enzyme inhibitor activity / biosynthetic process / protein glycosylation / transferase activity / GTP binding / enzyme binding / extracellular exosome / cytoplasm
Similarity search - Function
Mannose-1-phosphate guanyltransferase, N-terminal domain / : / Hexapeptide transferase, conserved site / Hexapeptide-repeat containing-transferases signature. / Nucleotidyl transferase domain / Nucleotidyl transferase / Hexapeptide repeat / Bacterial transferase hexapeptide (six repeats) / Nucleotide-diphospho-sugar transferases
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE / GUANOSINE-5'-TRIPHOSPHATE / Mannose-1-phosphate guanylyltransferase regulatory subunit alpha / Mannose-1-phosphate guanylyltransferase catalytic subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / cryo EM / Resolution: 3 Å
AuthorsZheng, L. / Liu, Z. / Wang, Y. / Yang, F. / Wang, J. / Qing, J. / Cai, X. / Mo, X. / Gao, N. / Jia, D.
Funding support1items
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, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 17, 2021Group: Database references / Structure summary / Category: citation / database_2 / struct
Item: _citation.title / _database_2.pdbx_DOI ..._citation.title / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct.title
Revision 1.2Dec 1, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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Assembly

Deposited unit
A: Mannose-1-phosphate guanyltransferase alpha
B: Mannose-1-phosphate guanyltransferase alpha
E: Mannose-1-phosphate guanyltransferase beta
C: Mannose-1-phosphate guanyltransferase alpha
D: Mannose-1-phosphate guanyltransferase alpha
F: Mannose-1-phosphate guanyltransferase beta
G: Mannose-1-phosphate guanyltransferase beta
I: Mannose-1-phosphate guanyltransferase beta
J: Mannose-1-phosphate guanyltransferase beta
K: Mannose-1-phosphate guanyltransferase beta
L: Mannose-1-phosphate guanyltransferase beta
H: Mannose-1-phosphate guanyltransferase beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)510,83724
Polymers504,39412
Non-polymers6,44212
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Mannose-1-phosphate guanyltransferase alpha / GDP-mannose pyrophosphorylase A / GMPP-alpha / GTP-mannose-1-phosphate guanylyltransferase alpha


Mass: 46341.961 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GMPPA / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q96IJ6
#2: Protein
Mannose-1-phosphate guanyltransferase beta / GDP-mannose pyrophosphorylase B / GTP-mannose-1-phosphate guanylyltransferase beta


Mass: 39878.316 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GMPPB / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: Q9Y5P6, mannose-1-phosphate guanylyltransferase
#3: Chemical ChemComp-GDD / GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE


Mass: 605.341 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H25N5O16P2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM
Has ligand of interestY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: YES
EM stainingType: NEGATIVE / Material: Uranyl acetate
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: DARK FIELD
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 106308 / Symmetry type: POINT

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