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- PDB-9e3a: Cryo-EM structure of PRMT5/WDR77 in complex with 6S complex (pICl... -

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Basic information

Entry
Database: PDB / ID: 9e3a
TitleCryo-EM structure of PRMT5/WDR77 in complex with 6S complex (pICln PBM local refinement)
Components
  • Methylosome protein WDR77
  • Methylosome subunit pICln
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / PRMT5 / Methyl transferase / WDR77 / arginine
Function / homology
Function and homology information


positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / peptidyl-arginine methylation / Golgi ribbon formation / negative regulation of epithelial cell proliferation involved in prostate gland development / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / histone arginine N-methyltransferase activity ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / peptidyl-arginine methylation / Golgi ribbon formation / negative regulation of epithelial cell proliferation involved in prostate gland development / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / histone arginine N-methyltransferase activity / epithelial cell proliferation involved in prostate gland development / histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / histone H3R8 methyltransferase activity / histone H3R26 methyltransferase activity / histone H3K37 methyltransferase activity / histone H4R3 methyltransferase activity / histone H4K12 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / pICln-Sm protein complex / positive regulation of mRNA splicing, via spliceosome / cell volume homeostasis / methyl-CpG binding / mRNA cis splicing, via spliceosome / histone H2AQ104 methyltransferase activity / chloride transport / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of gene expression via chromosomal CpG island methylation / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / liver regeneration / regulation of signal transduction by p53 class mediator / methyltransferase activity / spliceosomal complex / circadian regulation of gene expression / DNA-templated transcription termination / Regulation of TP53 Activity through Methylation / RMTs methylate histone arginines / protein polyubiquitination / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / cytoskeleton / transcription coactivator activity / cilium / chromatin remodeling / protein heterodimerization activity / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / Golgi apparatus / RNA binding / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
ICln / Protein ICln/Lot5/Saf5 / Regulator of volume decrease after cellular swelling / : / Protein arginine N-methyltransferase PRMT5 / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / PRMT5 arginine-N-methyltransferase ...ICln / Protein ICln/Lot5/Saf5 / Regulator of volume decrease after cellular swelling / : / Protein arginine N-methyltransferase PRMT5 / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 arginine-N-methyltransferase / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / PH-like domain superfamily / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Protein arginine N-methyltransferase 5 / Methylosome subunit pICln / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsJin, C.Y. / Hunkeler, M. / Fischer, E.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA262188 United States
CitationJournal: J Biol Chem / Year: 2025
Title: Substrate adaptors are flexible tethering modules that enhance substrate methylation by the arginine methyltransferase PRMT5.
Authors: Cyrus Y Jin / Moritz Hunkeler / Kathleen M Mulvaney / William R Sellers / Eric S Fischer /
Abstract: Protein arginine methyltransferase (PRMT) 5 is an essential arginine methyltransferase responsible for the majority of cellular symmetric dimethyl-arginine marks. PRMT5 uses substrate adaptors such ...Protein arginine methyltransferase (PRMT) 5 is an essential arginine methyltransferase responsible for the majority of cellular symmetric dimethyl-arginine marks. PRMT5 uses substrate adaptors such as pICln, RIOK1, and COPR5 to recruit and methylate a wide range of substrates. Although the substrate adaptors play important roles in substrate recognition, how they direct PRMT5 activity towards specific substrates remains incompletely understood. Using biochemistry and cryogenic electron microscopy, we show that these adaptors compete for the same binding site on PRMT5. We find that substrate adaptor and substrate complexes are bound to PRMT5 through two peptide motifs, enabling these adaptors to act as flexible tethering modules to enhance substrate methylation. Taken together, our results shed structural and mechanistic light on the PRMT5 substrate adaptor function and the biochemical nature of PRMT5 interactors.
History
DepositionOct 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
J: Protein arginine N-methyltransferase 5
K: Methylosome protein WDR77
L: Methylosome subunit pICln


Theoretical massNumber of molelcules
Total (without water)136,5063
Polymers136,5063
Non-polymers00
Water00
1


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

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Components

#1: Protein Protein arginine N-methyltransferase 5 / 72 kDa ICln-binding protein / Histone-arginine N-methyltransferase PRMT5 / Jak-binding protein 1 / ...72 kDa ICln-binding protein / Histone-arginine N-methyltransferase PRMT5 / Jak-binding protein 1 / Shk1 kinase-binding protein 1 homolog / SKB1Hs


Mass: 72766.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O14744, type II protein arginine methyltransferase
#2: Protein Methylosome protein WDR77 / Androgen receptor cofactor p44 / Methylosome protein 50 / MEP-50 / WD repeat-containing protein 77 / p44/Mep50


Mass: 37186.695 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR77, MEP50, WD45, HKMT1069, Nbla10071 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BQA1
#3: Protein Methylosome subunit pICln / Chloride channel / nucleotide sensitive 1A / Chloride conductance regulatory protein ICln / I(Cln) ...Chloride channel / nucleotide sensitive 1A / Chloride conductance regulatory protein ICln / I(Cln) / Chloride ion current inducer protein / ClCI / Reticulocyte pICln


Mass: 26552.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLNS1A, CLCI, ICLN / Production host: Escherichia coli (E. coli) / References: UniProt: P54105
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

Component
IDNameTypeEntity IDParent-IDSource
1PRMT5/WDR77 in complex with 6S (PBM local refinement)COMPLEXall0MULTIPLE SOURCES
2PRMT5/WDR77COMPLEX#1-#21RECOMBINANT
36S complexCOMPLEX#31RECOMBINANT
4Methylosome subunit pIClnCOMPLEX#33RECOMBINANT
5small nuclear ribonucleoproteins Sm D1, E, F, GCOMPLEX3RECOMBINANT
Molecular weightValue: 0.77 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Trichoplusia ni (cabbage looper)7111
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
Details: 30 mM HEPES pH 7.4, 150 mM NaCl, 3 mM TCEP, 3.33 mM sinefungin
Buffer component
IDConc.NameFormulaBuffer-ID
130 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
33 mMTCEPC9H15O6P1
43.33 mMsinefunginC15H23N7O51
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 283 K

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Electron microscopy imaging

MicroscopyModel: TFS TALOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 5 sec. / Electron dose: 53.112 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3615

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2SerialEM4.1image acquisition
4cryoSPARC4.4.1CTF correction
7UCSF ChimeraXmodel fitting
8ISOLDEmodel fitting
12cryoSPARC4.41classification
13cryoSPARC4.4.13D reconstruction
14PHENIX1.21.1_5286model refinement
15Coot0.9.6model refinement
Image processingDetails: motioncorrected on the fly by cryosparc live
CTF correctionDetails: as implemented in cryosparc live / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2100293 / Details: topaz
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 285661 / Symmetry type: POINT
Atomic model buildingB value: 98.6 / Protocol: OTHER / Space: REAL / Target criteria: real space correlation
Atomic model building

3D fitting-ID: 1 / Accession code: 6V0O / Initial refinement model-ID: 1 / PDB-ID: 6V0O

6v0o

/ Source name: PDB / Type: experimental model

IDPdb chain-IDChain-ID
1AA
2BB
3CC
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 116.31 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00324631
ELECTRON MICROSCOPYf_angle_d0.51956297
ELECTRON MICROSCOPYf_chiral_restr0.0423706
ELECTRON MICROSCOPYf_plane_restr0.0034809
ELECTRON MICROSCOPYf_dihedral_angle_d4.8235612

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