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- EMDB-72192: Structure of neurodevelopmental mutant AGO1 F180del in complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-72192
TitleStructure of neurodevelopmental mutant AGO1 F180del in complex with guide RNA
Map dataMap of human Argonaute1 F180Deletion
Sample
  • Complex: Complex of human Argonaute1 F180Deletion bound to a non-homogenous guide RNA
    • Protein or peptide: Protein argonaute-1
    • RNA: Non-homogenous guide RNA
KeywordsComplex / mutant / GENE REGULATION
Function / homology
Function and homology information


Post-transcriptional silencing by small RNAs / Competing endogenous RNAs (ceRNAs) regulate PTEN translation / Regulation of CDH11 mRNA translation by microRNAs / Regulation of NPAS4 mRNA translation / Regulation of PTEN mRNA translation / Small interfering RNA (siRNA) biogenesis / Regulation of CDH1 mRNA translation by microRNAs / Transcriptional Regulation by MECP2 / RISC-loading complex / miRNA metabolic process ...Post-transcriptional silencing by small RNAs / Competing endogenous RNAs (ceRNAs) regulate PTEN translation / Regulation of CDH11 mRNA translation by microRNAs / Regulation of NPAS4 mRNA translation / Regulation of PTEN mRNA translation / Small interfering RNA (siRNA) biogenesis / Regulation of CDH1 mRNA translation by microRNAs / Transcriptional Regulation by MECP2 / RISC-loading complex / miRNA metabolic process / RISC complex assembly / regulatory ncRNA-mediated post-transcriptional gene silencing / miRNA-mediated gene silencing by inhibition of translation / miRNA processing / pre-miRNA processing / Regulation of MITF-M-dependent genes involved in apoptosis / RISC complex / TGFBR3 expression / Regulation of RUNX1 Expression and Activity / miRNA binding / MicroRNA (miRNA) biogenesis / RNA polymerase II complex binding / Transcriptional Regulation by VENTX / nuclear-transcribed mRNA catabolic process / Regulation of MECP2 expression and activity / core promoter sequence-specific DNA binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Nuclear events stimulated by ALK signaling in cancer / regulation of mRNA stability / negative regulation of angiogenesis / TP53 Regulates Metabolic Genes / P-body / Transcriptional regulation by small RNAs / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / positive regulation of non-canonical NF-kappaB signal transduction / Oncogene Induced Senescence / MAPK6/MAPK4 signaling / Pre-NOTCH Transcription and Translation / cytoplasmic ribonucleoprotein granule / double-stranded RNA binding / Ca2+ pathway / Oxidative Stress Induced Senescence / Estrogen-dependent gene expression / single-stranded RNA binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / positive regulation of gene expression / positive regulation of transcription by RNA polymerase II / RNA binding / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Protein argonaute, Mid domain / Mid domain of argonaute / Argonaute linker 2 domain / Protein argonaute, N-terminal / Argonaute-like, PIWI domain / N-terminal domain of argonaute / Argonaute linker 2 domain / DUF1785 / Argonaute, linker 1 domain / Argonaute linker 1 domain ...Protein argonaute, Mid domain / Mid domain of argonaute / Argonaute linker 2 domain / Protein argonaute, N-terminal / Argonaute-like, PIWI domain / N-terminal domain of argonaute / Argonaute linker 2 domain / DUF1785 / Argonaute, linker 1 domain / Argonaute linker 1 domain / Piwi domain profile. / Piwi domain / Piwi domain / Piwi / PAZ domain superfamily / PAZ / PAZ domain / PAZ domain profile. / PAZ domain / Ribonuclease H superfamily / Ribonuclease H-like superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Trichoplusia ni (cabbage looper)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSavidge A / Adhav V / Shen Z / Fu T / Nakanishi K
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Neurodevelopmental disorder-linked Argonaute mutations permit delayed RISC formation and unusual shortening of miRNAs by 3'→5' trimming.
Authors: Andrew Savidge / Huaqun Zhang / Vishal Annasaheb Adhav / Audrey C Kehling / GeunYoung Sim / Zhangfei Shen / Tian-Min Fu / Kotaro Nakanishi /
Abstract: Mutations in Argonaute proteins (AGOs) cause Argonaute syndrome, a neurodevelopmental disorder (NDD), yet the underlying molecular mechanism remains unclear. We determined cryo-electron microscopy ...Mutations in Argonaute proteins (AGOs) cause Argonaute syndrome, a neurodevelopmental disorder (NDD), yet the underlying molecular mechanism remains unclear. We determined cryo-electron microscopy (cryo-EM) structures of wild-type (WT) AGO1 and the recurrent, severe causative ΔF180 mutant. AGO1(ΔF180) unexpectedly rearranges the hydrophobic core of the L1 domain to preserve the overall RNA-induced silencing complexes (RISC) architecture and recognize guide RNAs similarly to WT. Functionally, the mutant binds target RNAs like WT but more frequently retains passenger strands, implicating a defect in RISC assembly. Biochemical assays of ΔF180 and L190P mutants revealed normal duplex loading but impaired passenger ejection, exposing guide 3' ends to 3'→5' exonucleases and generating abnormally short ~11-nucleotide RNAs. In cells, AGO1(ΔF180), AGO1(G199S), and corresponding AGO2 mutants likewise produced truncated guides. Together, these findings support a model in which defective passenger ejection underlies the pathology of AGO-associated NDDs by rendering microRNAs bound to AGO syndrome mutants susceptible to aberrant 3' trimming.
History
DepositionAug 18, 2025-
Header (metadata) releaseNov 5, 2025-
Map releaseNov 5, 2025-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72192.png

Downloads & links

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Map

FileDownload / File: emd_72192.map.gz / Format: CCP4 / Size: 443.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of human Argonaute1 F180Deletion
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.45 Å/pix.
x 488 pix.
= 218.624 Å		0.45 Å/pix.
x 488 pix.
= 218.624 Å		0.45 Å/pix.
x 488 pix.
= 218.624 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.448 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016
Minimum - Maximum-0.11814273 - 0.1712723
Average (Standard dev.)0.00008994918 (±0.0041991738)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions488488488
Spacing488488488
CellA=B=C: 218.62401 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72192_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B human of Argonaute1 F180Deletion

Fileemd_72192_half_map_1.map
AnnotationHalf map B human of Argonaute1 F180Deletion
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A of human Argonaute1 F180Deletion

Fileemd_72192_half_map_2.map
AnnotationHalf map A of human Argonaute1 F180Deletion
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of human Argonaute1 F180Deletion bound to a non-homogenou...

EntireName: Complex of human Argonaute1 F180Deletion bound to a non-homogenous guide RNA
Components
  • Complex: Complex of human Argonaute1 F180Deletion bound to a non-homogenous guide RNA
    • Protein or peptide: Protein argonaute-1
    • RNA: Non-homogenous guide RNA

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Supramolecule #1: Complex of human Argonaute1 F180Deletion bound to a non-homogenou...

SupramoleculeName: Complex of human Argonaute1 F180Deletion bound to a non-homogenous guide RNA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 106 KDa

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Macromolecule #1: Protein argonaute-1

MacromoleculeName: Protein argonaute-1 / type: protein_or_peptide / ID: 1 / Details: N-terminal FLAG-tag, deletion of F180 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.733734 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GAMGSMDYKD DDDKMEAGPS GAAAGAYLPP LQQVFQAPRR PGIGTVGKPI KLLANYFEVD IPKIDVYHYE VDIKPDKCPR RVNREVVEY MVQHFKPQIF GDRKPVYDGK KNIYTVTALP IGNERVDFEV TIPGEGKDRI FKVSIKWLAI VSWRMLHEAL V SGQIPVPL ...String:
GAMGSMDYKD DDDKMEAGPS GAAAGAYLPP LQQVFQAPRR PGIGTVGKPI KLLANYFEVD IPKIDVYHYE VDIKPDKCPR RVNREVVEY MVQHFKPQIF GDRKPVYDGK KNIYTVTALP IGNERVDFEV TIPGEGKDRI FKVSIKWLAI VSWRMLHEAL V SGQIPVPL ESVQALDVAM RHLASMRYTP VGRSFSPPEG YYHPLGGGRE VWFGFHQSVR PAMWKMMLNI DVSATAFYKA QP VIEFMCE VLDIRNIDEQ PKPLTDSQRV RFTKEIKGLK VEVTHCGQMK RKYRVCNVTR RPASHQTFPL QLESGQTVEC TVA QYFKQK YNLQLKYPHL PCLQVGQEQK HTYLPLEVCN IVAGQRCIKK LTDNQTSTMI KATARSAPDR QEEISRLMKN ASYN LDPYI QEFGIKVKDD MTEVTGRVLP APILQYGGRN RAIATPNQGV WDMRGKQFYN GIEIKVWAIA CFAPQKQCRE EVLKN FTDQ LRKISKDAGM PIQGQPCFCK YAQGADSVEP MFRHLKNTYS GLQLIIVILP GKTPVYAEVK RVGDTLLGMA TQCVQV KNV VKTSPQTLSN LCLKINVKLG GINNILVPHQ RSAVFQQPVI FLGADVTHPP AGDGKKPSIT AVVGSMDAHP SRYCATV RV QRPRQEIIED LSYMVRELLI QFYKSTRFKP TRIIFYRDGV PEGQLPQILH YELLAIRDAC IKLEKDYQPG ITYIVVQK R HHTRLFCADK NERIGKSGNI PAGTTVDTNI THPFEFDFYL CSHAGIQGTS RPSHYYVLWD DNRFTADELQ ILTYQLCHT YVRCTRSVSI PAPAYYARLV AFRARYHLVD KEHDSGEGSH ISGQSNGRDP QALAKAVQVH QDTLRTMYFA

UniProtKB: Protein argonaute-1

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Macromolecule #2: Non-homogenous guide RNA

MacromoleculeName: Non-homogenous guide RNA / type: rna / ID: 2 / Number of copies: 1
Source (natural)Organism: Trichoplusia ni (cabbage looper)
Molecular weightTheoretical: 2.588689 KDa
SequenceString:
AAAAAAAA

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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

Concentration0.35 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMC8H18N2O4SHEPES pH 7.5
150.0 mMNaClsodium chloride
0.5 mMC9H15O6PTCEP
2.0 mMC16H18N2Na2O14S2BS3
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS TITAN THEMIS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 2.75 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: -2.5 µm / Nominal defocus min: -0.5 µm

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.7.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4kxt


Details: The deletion of F180 was done in Coot, and the resulting model was used for reconstruction.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7.0) / Number images used: 435426
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.0)
FSC plot (resolution estimation)

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