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- PDB-8p7d: CryoEM structure of METTL6 tRNA SerRS complex in a 1:1:2 stoichiometry -

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Basic information

Entry
Database: PDB / ID: 8p7d
TitleCryoEM structure of METTL6 tRNA SerRS complex in a 1:1:2 stoichiometry
Components
  • Serine tRNA
  • Serine--tRNA ligase, cytoplasmic
  • tRNA N(3)-methylcytidine methyltransferase METTL6
KeywordsRNA BINDING PROTEIN / METTL6 / tRNA / SerRS / Serine tRNA / 3-Methylcytosine
Function / homology
Function and homology information


selenocysteine-tRNA ligase activity / tRNA (cytidine-3-)-methyltransferase activity / negative regulation of vascular endothelial growth factor production / selenocysteine incorporation / serine-tRNA ligase / serine-tRNA ligase activity / seryl-tRNA aminoacylation / Cytosolic tRNA aminoacylation / tRNA modification / tRNA methylation ...selenocysteine-tRNA ligase activity / tRNA (cytidine-3-)-methyltransferase activity / negative regulation of vascular endothelial growth factor production / selenocysteine incorporation / serine-tRNA ligase / serine-tRNA ligase activity / seryl-tRNA aminoacylation / Cytosolic tRNA aminoacylation / tRNA modification / tRNA methylation / Selenocysteine synthesis / Transferases; Transferring one-carbon groups; Methyltransferases / negative regulation of angiogenesis / molecular adaptor activity / cytoplasmic translation / tRNA binding / translation / RNA polymerase II cis-regulatory region sequence-specific DNA binding / enzyme binding / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / extracellular exosome / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
tRNA N(3)-methylcytidine methyltransferase METTL2/6/8-like / Serine-tRNA synthetase, type1, N-terminal / Seryl-tRNA synthetase N-terminal domain / Serine-tRNA ligase, type1 / Serine-tRNA ligase catalytic core domain / Serine-tRNA synthetase, type1, N-terminal domain superfamily / Class I and II aminoacyl-tRNA synthetase, tRNA-binding arm / Methyltransferase type 12 / Methyltransferase domain / Aminoacyl-tRNA synthetase, class II (G/ P/ S/T) ...tRNA N(3)-methylcytidine methyltransferase METTL2/6/8-like / Serine-tRNA synthetase, type1, N-terminal / Seryl-tRNA synthetase N-terminal domain / Serine-tRNA ligase, type1 / Serine-tRNA ligase catalytic core domain / Serine-tRNA synthetase, type1, N-terminal domain superfamily / Class I and II aminoacyl-tRNA synthetase, tRNA-binding arm / Methyltransferase type 12 / Methyltransferase domain / Aminoacyl-tRNA synthetase, class II (G/ P/ S/T) / tRNA synthetase class II core domain (G, H, P, S and T) / Aminoacyl-tRNA synthetase, class II / Aminoacyl-transfer RNA synthetases class-II family profile. / Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / RNA / RNA (> 10) / Serine--tRNA ligase, cytoplasmic / tRNA N(3)-cytidine methyltransferase METTL6
Similarity search - Component
Biological speciesHomo sapiens (human)
Trichoplusia ni (cabbage looper)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsThroll, P. / Dolce, L.G. / Kowalinski, E.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural basis of tRNA recognition by the mC RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase.
Authors: Philipp Throll / Luciano G Dolce / Palma Rico-Lastres / Katharina Arnold / Laura Tengo / Shibom Basu / Stefanie Kaiser / Robert Schneider / Eva Kowalinski /
Abstract: Methylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (mC) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification ...Methylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (mC) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification can cause aggressive cancers and metabolic disturbances. Here, we report the cryo-electron microscopy structure of the human mC tRNA methyltransferase METTL6 in complex with seryl-tRNA synthetase (SerRS) and their common substrate tRNA. Through the complex structure, we identify the tRNA-binding domain of METTL6. We show that SerRS acts as the tRNA substrate selection factor for METTL6. We demonstrate that SerRS augments the methylation activity of METTL6 and that direct contacts between METTL6 and SerRS are necessary for efficient tRNA methylation. Finally, on the basis of the structure of METTL6 in complex with SerRS and tRNA, we postulate a universal tRNA-binding mode for mC RNA methyltransferases, including METTL2 and METTL8, suggesting that these mammalian paralogs use similar ways to engage their respective tRNA substrates and cofactors.
History
DepositionMay 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.2Jul 10, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _em_admin.last_update
Revision 1.3Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / em_admin / pdbx_entry_details
Item: _chem_comp.mon_nstd_flag / _chem_comp.type ..._chem_comp.mon_nstd_flag / _chem_comp.type / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: tRNA N(3)-methylcytidine methyltransferase METTL6
B: Serine--tRNA ligase, cytoplasmic
D: Serine--tRNA ligase, cytoplasmic
R: Serine tRNA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,1008
Polymers178,6434
Non-polymers4574
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 3 molecules ABD

#1: Protein tRNA N(3)-methylcytidine methyltransferase METTL6 / Methyltransferase-like protein 6 / hMETTL6


Mass: 33296.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METTL6 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q8TCB7, Transferases; Transferring one-carbon groups; Methyltransferases
#2: Protein Serine--tRNA ligase, cytoplasmic / Seryl-tRNA synthetase / SerRS / Seryl-tRNA(Ser/Sec) synthetase


Mass: 58863.211 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SARS1, SARS, SERS / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P49591, serine-tRNA ligase

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RNA chain , 1 types, 1 molecules R

#3: RNA chain Serine tRNA


Mass: 27620.635 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Trichoplusia ni (cabbage looper)

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Non-polymers , 3 types, 5 molecules

#4: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: METTL6 tRNA SerRS complex in a 1:1:2 stoichiometry / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 63.27 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.16_3549: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 35788 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.02110066
ELECTRON MICROSCOPYf_angle_d1.55714017
ELECTRON MICROSCOPYf_dihedral_angle_d14.2625745
ELECTRON MICROSCOPYf_chiral_restr0.1071614
ELECTRON MICROSCOPYf_plane_restr0.0071484

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