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Yorodumi- EMDB-26035: Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptid... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-26035 | |||||||||||||||
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Title | Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein poly-PR | |||||||||||||||
Map data | Rabbit 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein polyPR | |||||||||||||||
Sample |
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Keywords | ribosomal binding peptide / ALS/FTD-associated dipeptide repeat protein / RIBOSOME | |||||||||||||||
Function / homology | Function and homology information ribosomal subunit / mammalian oogenesis stage / activation-induced cell death of T cells / regulation of G1 to G0 transition / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / G1 to G0 transition / T cell proliferation involved in immune response ...ribosomal subunit / mammalian oogenesis stage / activation-induced cell death of T cells / regulation of G1 to G0 transition / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / G1 to G0 transition / T cell proliferation involved in immune response / erythrocyte development / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / phagocytic cup / TOR signaling / ribosomal small subunit export from nucleus / translation regulator activity / cellular response to actinomycin D / 90S preribosome / rough endoplasmic reticulum / gastrulation / MDM2/MDM4 family protein binding / cytosolic ribosome / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / rescue of stalled ribosome / class I DNA-(apurinic or apyrimidinic site) endonuclease activity / DNA-(apurinic or apyrimidinic site) lyase / negative regulation of ubiquitin-dependent protein catabolic process / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / ribosomal large subunit biogenesis / maturation of SSU-rRNA / positive regulation of apoptotic signaling pathway / positive regulation of translation / small-subunit processome / placenta development / protein kinase C binding / positive regulation of protein-containing complex assembly / G1/S transition of mitotic cell cycle / cellular response to gamma radiation / mRNA 5'-UTR binding / transcription coactivator binding / modification-dependent protein catabolic process / cytoplasmic ribonucleoprotein granule / spindle / rRNA processing / protein tag activity / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit rRNA binding / positive regulation of canonical Wnt signaling pathway / rhythmic process / ribosome binding / glucose homeostasis / regulation of translation / T cell differentiation in thymus / 5S rRNA binding / cell body / large ribosomal subunit rRNA binding / small ribosomal subunit / cytosolic small ribosomal subunit / perikaryon / cytosolic large ribosomal subunit / cytoplasmic translation / mitochondrial inner membrane / tRNA binding / postsynaptic density / cell differentiation / protein stabilization / rRNA binding / ribosome / protein ubiquitination / structural constituent of ribosome / ribonucleoprotein complex / translation / positive regulation of protein phosphorylation / positive regulation of apoptotic process / cell cycle / cell division / DNA repair / mRNA binding / apoptotic process / synapse / ubiquitin protein ligase binding / dendrite / positive regulation of cell population proliferation / positive regulation of gene expression / nucleolus / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / Golgi apparatus / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / DNA binding / RNA binding / zinc ion binding / nucleoplasm / metal ion binding / nucleus / cytosol Similarity search - Function | |||||||||||||||
Biological species | Oryctolagus cuniculus (rabbit) / Saccharomyces cerevisiae (brewer's yeast) / Escherichia coli K-12 (bacteria) / Homo sapiens (human) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||||||||
Authors | Loveland AB / Svidritskiy E / Susorov D / Lee S / Park A / Zvornicanin S / Demo G / Gao FB / Korostelev AA | |||||||||||||||
Funding support | United States, 4 items
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Citation | Journal: Nat Commun / Year: 2022 Title: Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Authors: Anna B Loveland / Egor Svidritskiy / Denis Susorov / Soojin Lee / Alexander Park / Sarah Zvornicanin / Gabriel Demo / Fen-Biao Gao / Andrei A Korostelev / Abstract: Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ...Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD. | |||||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_26035.map.gz | 794.3 MB | EMDB map data format | |
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Header (meta data) | emd-26035-v30.xml emd-26035.xml | 99.5 KB 99.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_26035_fsc.xml | 20.7 KB | Display | FSC data file |
Images | emd_26035.png | 136.3 KB | ||
Filedesc metadata | emd-26035.cif.gz | 18.6 KB | ||
Others | emd_26035_half_map_1.map.gz emd_26035_half_map_2.map.gz | 144.7 MB 144.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-26035 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-26035 | HTTPS FTP |
-Related structure data
Related structure data | 7toqMC 7tooC 7topC 7torC 7tosC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_26035.map.gz / Format: CCP4 / Size: 857.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Rabbit 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein polyPR | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.87 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half map 2
File | emd_26035_half_map_1.map | ||||||||||||
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Annotation | Half map 2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 1
File | emd_26035_half_map_2.map | ||||||||||||
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Annotation | Half map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Mamalian 80S ribosome bound with the ALS/FTD-associated dipeptide...
+Supramolecule #1: Mamalian 80S ribosome bound with the ALS/FTD-associated dipeptide...
+Macromolecule #1: 18S rRNA
+Macromolecule #2: 28S rRNA
+Macromolecule #3: 5.8S rRNA
+Macromolecule #4: 5S rRNA
+Macromolecule #82: RNA (5'-R(*CP*AP*CP*AP*UP*GP*UP*UP*CP*C)-3')
+Macromolecule #84: tRNAfMet
+Macromolecule #5: uL2
+Macromolecule #6: 60S ribosomal protein L3
+Macromolecule #7: 60S ribosomal protein L4
+Macromolecule #8: 60S ribosomal protein L5
+Macromolecule #9: 60S ribosomal protein L6
+Macromolecule #10: uL30
+Macromolecule #11: eL8
+Macromolecule #12: 60S ribosomal protein L9
+Macromolecule #13: Ribosomal protein L10
+Macromolecule #14: 60S ribosomal protein L11
+Macromolecule #15: 60S ribosomal protein L12
+Macromolecule #16: eL13
+Macromolecule #17: 60S ribosomal protein L14
+Macromolecule #18: 60S ribosomal protein L15
+Macromolecule #19: uL13
+Macromolecule #20: 60S ribosomal protein L17
+Macromolecule #21: eL18
+Macromolecule #22: 60S ribosomal protein L19
+Macromolecule #23: eL20
+Macromolecule #24: 60S ribosomal protein L21
+Macromolecule #25: eL22
+Macromolecule #26: 60S ribosomal protein L23
+Macromolecule #27: Ribosomal protein L24
+Macromolecule #28: uL23
+Macromolecule #29: 60S ribosomal protein L26
+Macromolecule #30: 60S ribosomal protein L27
+Macromolecule #31: 60S ribosomal protein L27a
+Macromolecule #32: eL29
+Macromolecule #33: eL30
+Macromolecule #34: 60S ribosomal protein L31
+Macromolecule #35: 60S ribosomal protein L32
+Macromolecule #36: 60S ribosomal protein L35a
+Macromolecule #37: 60S ribosomal protein L34
+Macromolecule #38: 60S ribosomal protein L35
+Macromolecule #39: 60S ribosomal protein L36
+Macromolecule #40: 60S ribosomal protein L37
+Macromolecule #41: eL38
+Macromolecule #42: eL39
+Macromolecule #43: eL40
+Macromolecule #44: eL41
+Macromolecule #45: eL42
+Macromolecule #46: 60S ribosomal protein L37a
+Macromolecule #47: 60S acidic ribosomal protein P0
+Macromolecule #48: Receptor of activated protein C kinase 1
+Macromolecule #49: 40S_SA_C domain-containing protein
+Macromolecule #50: 40S ribosomal protein S3a
+Macromolecule #51: 40S ribosomal protein S2
+Macromolecule #52: 40S ribosomal protein S3
+Macromolecule #53: 40S ribosomal protein S4
+Macromolecule #54: Ribosomal protein S5
+Macromolecule #55: 40S ribosomal protein S6
+Macromolecule #56: eS7
+Macromolecule #57: 40S ribosomal protein S8
+Macromolecule #58: 40S ribosomal protein S9
+Macromolecule #59: 40S ribosomal protein S10
+Macromolecule #60: 40S ribosomal protein S11
+Macromolecule #61: 40S ribosomal protein S12
+Macromolecule #62: 40S ribosomal protein S13
+Macromolecule #63: 40S ribosomal protein S14
+Macromolecule #64: 40S ribosomal protein S15
+Macromolecule #65: uS9
+Macromolecule #66: 40S ribosomal protein S17
+Macromolecule #67: 40S ribosomal protein S18
+Macromolecule #68: eS19
+Macromolecule #69: 40S ribosomal protein S20
+Macromolecule #70: eS21
+Macromolecule #71: 40S ribosomal protein S15a
+Macromolecule #72: 40S ribosomal protein S23
+Macromolecule #73: 40S ribosomal protein S24
+Macromolecule #74: 40S ribosomal protein S25
+Macromolecule #75: eS26
+Macromolecule #76: 40S ribosomal protein S27
+Macromolecule #77: 40S ribosomal protein S28
+Macromolecule #78: 40S ribosomal protein S29
+Macromolecule #79: 40S ribosomal protein S30
+Macromolecule #80: 40S ribosomal protein S27a
+Macromolecule #81: 60S ribosomal protein L28
+Macromolecule #83: PR20, ALS/FTD dipeptide repeat protein
+Macromolecule #85: ZINC ION
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7 |
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.5 µm |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 30.0 e/Å2 |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |