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- EMDB-26991: Cryo-EM structure of human METTL1-WDR4-tRNA(Val) complex -

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Basic information

Entry
Database: EMDB / ID: EMD-26991
TitleCryo-EM structure of human METTL1-WDR4-tRNA(Val) complex
Map dataMETTL1-WDR4-tRNA(Val) complex
Sample
  • Complex: METTL1-WDR4-tRNA_Val
    • Complex: tRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
      • Protein or peptide: tRNA (guanine-N(7)-)-methyltransferase
      • Protein or peptide: tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
    • Complex: RNA
      • RNA: tRNA-Val-TAC-2-1
KeywordsEpitranscriptome / m7G / METTL1 / Methylation / Methyltransferase / TRANSFERASE / TRANSFERASE-RNA complex
Function / homology
Function and homology information


internal mRNA (guanine-N7-)-methyltransferase activity / tRNA stabilization / tRNA (m7G46) methyltransferase complex / tRNA (guanine-N7)-methylation / RNA (guanine-N7)-methylation / tRNA (guanine46-N7)-methyltransferase / tRNA (guanine(46)-N7)-methyltransferase activity / tRNA methyltransferase activator activity / tRNA methyltransferase complex / tRNA modification in the nucleus and cytosol ...internal mRNA (guanine-N7-)-methyltransferase activity / tRNA stabilization / tRNA (m7G46) methyltransferase complex / tRNA (guanine-N7)-methylation / RNA (guanine-N7)-methylation / tRNA (guanine46-N7)-methyltransferase / tRNA (guanine(46)-N7)-methyltransferase activity / tRNA methyltransferase activator activity / tRNA methyltransferase complex / tRNA modification in the nucleus and cytosol / tRNA methylation / tRNA modification / enzyme activator activity / Transferases; Transferring one-carbon groups; Methyltransferases / chromosome / tRNA binding / DNA damage response / nucleolus / nucleoplasm / nucleus / cytosol
Similarity search - Function
tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit / tRNA (guanine-N-7) methyltransferase catalytic subunit Trm8, eukaryote / SAM-dependent methyltransferase TRMB-type domain profile. / tRNA (guanine-N-7) methyltransferase, Trmb type / Putative methyltransferase / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat ...tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit / tRNA (guanine-N-7) methyltransferase catalytic subunit Trm8, eukaryote / SAM-dependent methyltransferase TRMB-type domain profile. / tRNA (guanine-N-7) methyltransferase, Trmb type / Putative methyltransferase / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4 / tRNA (guanine-N(7)-)-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsLi J / Wang L / Fontana P / Hunkeler M / Roy-Burman SS / Wu H / Fischer ES / Gregory RI
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R35CA232115 United States
CitationJournal: Nature / Year: 2023
Title: Structural basis of regulated mG tRNA modification by METTL1-WDR4.
Authors: Jiazhi Li / Longfei Wang / Quentin Hahn / Radosław P Nowak / Thibault Viennet / Esteban A Orellana / Shourya S Roy Burman / Hong Yue / Moritz Hunkeler / Pietro Fontana / Hao Wu / Haribabu ...Authors: Jiazhi Li / Longfei Wang / Quentin Hahn / Radosław P Nowak / Thibault Viennet / Esteban A Orellana / Shourya S Roy Burman / Hong Yue / Moritz Hunkeler / Pietro Fontana / Hao Wu / Haribabu Arthanari / Eric S Fischer / Richard I Gregory /
Abstract: Chemical modifications of RNA have key roles in many biological processes. N-methylguanosine (mG) is required for integrity and stability of a large subset of tRNAs. The methyltransferase 1-WD repeat- ...Chemical modifications of RNA have key roles in many biological processes. N-methylguanosine (mG) is required for integrity and stability of a large subset of tRNAs. The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types. Mutations in WDR4 cause human developmental phenotypes including microcephaly. How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive. Here we show,  through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.
History
DepositionMay 14, 2022-
Header (metadata) releaseDec 7, 2022-
Map releaseDec 7, 2022-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26991.png

Downloads & links

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Map

FileDownload / File: emd_26991.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMETTL1-WDR4-tRNA(Val) complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.308
Minimum - Maximum-2.4018455 - 3.5969806
Average (Standard dev.)-0.0001636511 (±0.041395854)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 264.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: METTL1-WDR4-tRNA(Val) complex

Fileemd_26991_half_map_1.map
AnnotationMETTL1-WDR4-tRNA(Val) complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: METTL1-WDR4-tRNA(Val) complex

Fileemd_26991_half_map_2.map
AnnotationMETTL1-WDR4-tRNA(Val) complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : METTL1-WDR4-tRNA_Val

EntireName: METTL1-WDR4-tRNA_Val
Components
  • Complex: METTL1-WDR4-tRNA_Val
    • Complex: tRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
      • Protein or peptide: tRNA (guanine-N(7)-)-methyltransferase
      • Protein or peptide: tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
    • Complex: RNA
      • RNA: tRNA-Val-TAC-2-1

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Supramolecule #1: METTL1-WDR4-tRNA_Val

SupramoleculeName: METTL1-WDR4-tRNA_Val / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: tRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine-N(7)-)-meth...

SupramoleculeName: tRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: RNA

SupramoleculeName: RNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3

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Macromolecule #1: tRNA (guanine-N(7)-)-methyltransferase

MacromoleculeName: tRNA (guanine-N(7)-)-methyltransferase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: tRNA (guanine46-N7)-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.516012 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MAAETRNVAG AEAPPPQKRY YRQRAHSNPM ADHTLRYPVK PEEMDWSELY PEFFAPLTQN QSHDDPKDKK EKRAQAQVEF ADIGCGYGG LLVELSPLFP DTLILGLEIR VKVSDYVQDR IRALRAAPAG GFQNIACLRS NAMKHLPNFF YKGQLTKMFF L FPDPHFKR ...String:
MAAETRNVAG AEAPPPQKRY YRQRAHSNPM ADHTLRYPVK PEEMDWSELY PEFFAPLTQN QSHDDPKDKK EKRAQAQVEF ADIGCGYGG LLVELSPLFP DTLILGLEIR VKVSDYVQDR IRALRAAPAG GFQNIACLRS NAMKHLPNFF YKGQLTKMFF L FPDPHFKR TKHKWRIISP TLLAEYAYVL RVGGLVYTIT DVLELHDWMC THFEEHPLFE RVPLEDLSED PVVGHLGTST EE GKKVLRN GGKNFPAIFR RIQDPVLQAV TSQTSLPGH

UniProtKB: tRNA (guanine-N(7)-)-methyltransferase

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Macromolecule #2: tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4

MacromoleculeName: tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.363516 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH SQDPNSMAGS VGLALCGQTL VVRGGSRFLA TSIASSDDDS LFIYDCSAAE KKSQENKGED APLDQGSGAI LASTFSKSG SYFALTDDSK RLILFRTKPW QCLSVRTVAR RCTALTFIAS EEKVLVADKS GDVYSFSVLE PHGCGRLELG H LSMLLDVA ...String:
MGSSHHHHHH SQDPNSMAGS VGLALCGQTL VVRGGSRFLA TSIASSDDDS LFIYDCSAAE KKSQENKGED APLDQGSGAI LASTFSKSG SYFALTDDSK RLILFRTKPW QCLSVRTVAR RCTALTFIAS EEKVLVADKS GDVYSFSVLE PHGCGRLELG H LSMLLDVA VSPDDRFILT ADRDEKIRVS WAAAPHSIES FCLGHTEFVS RISVVPTQPG LLLSSSGDGT LRLWEYRSGR QL HCCHLAS LQELVDPQAP QKFAASRIAF WCQENCVALL CDGTPVVYIF QLDARRQQLV YRQQLAFQHQ VWDVAFEETQ GLW VLQDCQ EAPLVLYRPV GDQWQSVPES TVLKKVSGVL RGNWAMLEGS AGADASFSSL YKATFDNVTS YLKKKEERLQ QQLE KKQRR RSPPPGPDGH AKKMRPGEAT LSC

UniProtKB: tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4

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Macromolecule #3: tRNA-Val-TAC-2-1

MacromoleculeName: tRNA-Val-TAC-2-1 / type: rna / ID: 3 / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.451889 KDa
SequenceString:
GGUUCCAUAG UGUAGCGGUU AUCACGUCUG CUUUACACGC AGAAGGUCCU GGGUUCGAGC CCCAGUGGAA CCA

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 51.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 11597
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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