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- PDB-8qfc: UFL1 E3 ligase bound 60S ribosome -

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Basic information

Entry
Database: PDB / ID: 8qfc
TitleUFL1 E3 ligase bound 60S ribosome
Components
  • 60S ribosomal protein L10a
  • CDK5 regulatory subunit-associated protein 3
  • DDRGK domain-containing protein 1
  • E3 UFM1-protein ligase 1
  • Ubiquitin-fold modifier 1
KeywordsLIGASE / UFM1 / Ribosome / Complex
Function / homology
Function and homology information


positive regulation of I-kappaB phosphorylation / UFM1 ligase activity / UFM1-modified protein reader activity / positive regulation of reticulophagy / regulation of phosphatase activity / apoptotic nuclear changes / definitive erythrocyte differentiation / UFM1 transferase activity / negative regulation of protein serine/threonine kinase activity / positive regulation of protein localization to endoplasmic reticulum ...positive regulation of I-kappaB phosphorylation / UFM1 ligase activity / UFM1-modified protein reader activity / positive regulation of reticulophagy / regulation of phosphatase activity / apoptotic nuclear changes / definitive erythrocyte differentiation / UFM1 transferase activity / negative regulation of protein serine/threonine kinase activity / positive regulation of protein localization to endoplasmic reticulum / protein K69-linked ufmylation / protein ufmylation / negative regulation of protein kinase activity by regulation of protein phosphorylation / : / positive regulation of plasma cell differentiation / negative regulation of IRE1-mediated unfolded protein response / regulation of proteasomal ubiquitin-dependent protein catabolic process / positive regulation of cell cycle G1/S phase transition / negative regulation of T cell mediated immune response to tumor cell / protein localization to endoplasmic reticulum / negative regulation of T cell activation / regulation of intracellular estrogen receptor signaling pathway / positive regulation of proteasomal protein catabolic process / mitotic G2/M transition checkpoint / regulation of cyclin-dependent protein serine/threonine kinase activity / cartilage development / Transferases; Acyltransferases; Aminoacyltransferases / regulation of canonical NF-kappaB signal transduction / response to L-glutamate / ribosome disassembly / mitogen-activated protein kinase binding / regulation of neuron differentiation / reticulophagy / : / negative regulation of PERK-mediated unfolded protein response / mitotic G2 DNA damage checkpoint signaling / negative regulation of MAP kinase activity / negative regulation of protein phosphorylation / ubiquitin-like protein ligase binding / positive regulation of glial cell proliferation / Peptide chain elongation / Selenocysteine synthesis / RHOA GTPase cycle / Formation of a pool of free 40S subunits / Eukaryotic Translation Termination / hematopoietic stem cell differentiation / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency / NF-kappaB binding / Viral mRNA Translation / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / positive regulation of signal transduction by p53 class mediator / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / Major pathway of rRNA processing in the nucleolus and cytosol / endoplasmic reticulum unfolded protein response / ubiquitin-like ligase-substrate adaptor activity / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / endomembrane system / positive regulation of autophagy / MDM2/MDM4 family protein binding / negative regulation of protein ubiquitination / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / regulation of mitotic cell cycle / rescue of stalled cytosolic ribosome / cytosolic ribosome / response to endoplasmic reticulum stress / cyclin binding / DNA damage checkpoint signaling / positive regulation of protein ubiquitination / erythrocyte differentiation / liver development / regulation of protein stability / : / negative regulation of protein catabolic process / brain development / positive regulation of protein localization to nucleus / Regulation of expression of SLITs and ROBOs / osteoblast differentiation / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / regulation of protein localization / site of double-strand break / regulation of inflammatory response / cytosolic large ribosomal subunit / response to ethanol / cytoplasmic translation / mitochondrial outer membrane / positive regulation of canonical NF-kappaB signal transduction / cell population proliferation / neuron projection / postsynaptic density / protein stabilization / positive regulation of cell migration / structural constituent of ribosome / translation / intracellular membrane-bounded organelle / negative regulation of gene expression / focal adhesion / DNA repair
Similarity search - Function
CDK5 regulatory subunit-associated protein 3 / CDK5 regulatory subunit-associated protein 3 / DDRGK domain containing protein / : / DDRGK domain / DDRGK / E3 UFM1-protein ligase 1 / : / : / : ...CDK5 regulatory subunit-associated protein 3 / CDK5 regulatory subunit-associated protein 3 / DDRGK domain containing protein / : / DDRGK domain / DDRGK / E3 UFM1-protein ligase 1 / : / : / : / E3 UFM1-protein ligase 1 / E3 UFM1-protein ligase 1-like domain / E3 UFM1-protein ligase 1 C-terminal domain / Ubiquitin-fold modifier 1 / Ubiquitin fold modifier 1 protein / Ribosomal protein L1, conserved site / Ribosomal protein L1 signature. / Ribosomal protein L1 / Ribosomal protein L1, 3-layer alpha/beta-sandwich / Ribosomal protein L1-like / Ribosomal protein L1/ribosomal biogenesis protein / Ribosomal protein L1p/L10e family / : / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Ubiquitin-fold modifier 1 / E3 UFM1-protein ligase 1 / Large ribosomal subunit protein uL1 / DDRGK domain-containing protein 1 / CDK5 regulatory subunit-associated protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMakhlouf, L. / Zeqiraj, E. / Kulathu, Y.
Funding support United Kingdom, European Union, 4items
OrganizationGrant numberCountry
Wellcome Trust222531/Z/21/Z United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/T008172/1 United Kingdom
European Research Council (ERC)677623European Union
Medical Research Council (MRC, United Kingdom)MC_UU_00018/3 United Kingdom
CitationJournal: Nature / Year: 2024
Title: The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
Authors: Linda Makhlouf / Joshua J Peter / Helge M Magnussen / Rohan Thakur / David Millrine / Thomas C Minshull / Grace Harrison / Joby Varghese / Frederic Lamoliatte / Martina Foglizzo / Thomas ...Authors: Linda Makhlouf / Joshua J Peter / Helge M Magnussen / Rohan Thakur / David Millrine / Thomas C Minshull / Grace Harrison / Joby Varghese / Frederic Lamoliatte / Martina Foglizzo / Thomas Macartney / Antonio N Calabrese / Elton Zeqiraj / Yogesh Kulathu /
Abstract: Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24). This modification, ...Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24). This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. ). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S-SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a 'writer' to a 'reader' module that recognizes its product-UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.
History
DepositionSep 4, 2023Deposition site: PDBE / Processing site: PDBE
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 60S ribosomal protein L10a
B: E3 UFM1-protein ligase 1
C: CDK5 regulatory subunit-associated protein 3
D: DDRGK domain-containing protein 1
E: Ubiquitin-fold modifier 1


Theoretical massNumber of molelcules
Total (without water)217,8115
Polymers217,8115
Non-polymers00
Water00
1


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

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Components

#1: Protein 60S ribosomal protein L10a / CSA-19 / Large ribosomal subunit protein uL1 / Neural precursor cell expressed developmentally down- ...CSA-19 / Large ribosomal subunit protein uL1 / Neural precursor cell expressed developmentally down-regulated protein 6 / NEDD-6


Mass: 24879.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPL10A, NEDD6 / Production host: Escherichia coli (E. coli) / References: UniProt: P62906
#2: Protein E3 UFM1-protein ligase 1 / E3 UFM1-protein transferase 1 / Multiple alpha-helix protein located at ER / Novel LZAP-binding ...E3 UFM1-protein transferase 1 / Multiple alpha-helix protein located at ER / Novel LZAP-binding protein / Regulator of C53/LZAP and DDRGK1


Mass: 91591.234 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UFL1, KIAA0776, MAXER, NLBP, RCAD / Production host: Escherichia coli (E. coli)
References: UniProt: O94874, Transferases; Acyltransferases; Aminoacyltransferases
#3: Protein CDK5 regulatory subunit-associated protein 3 / CDK5 activator-binding protein C53 / LXXLL/leucine-zipper-containing ARF-binding protein / Protein HSF-27


Mass: 57458.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK5RAP3, IC53, LZAP, MSTP016, OK/SW-cl.114, PP1553 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96JB5
#4: Protein DDRGK domain-containing protein 1 / Dashurin / UFM1-binding and PCI domain-containing protein 1


Mass: 34644.445 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDRGK1, C20orf116, UFBP1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96HY6
#5: Protein Ubiquitin-fold modifier 1


Mass: 9236.628 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UFM1 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A8C2YGR4
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: UFM1 ribosome E3 ligase complex bound to 60S ribosome / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Details: 25 mM HEPES pH 7.5, 50 mM KCl, 5 mM MgCl2, 2 mM DTT
SpecimenConc.: 7.7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 200 nm
Image recordingAverage exposure time: 2.67 sec. / Electron dose: 33.4 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 59394
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
2EPU3.2.0image acquisition
4CTFFIND4CTF correction
9PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 299008 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411126
ELECTRON MICROSCOPYf_angle_d0.53215139
ELECTRON MICROSCOPYf_dihedral_angle_d4.3341565
ELECTRON MICROSCOPYf_chiral_restr0.0381873
ELECTRON MICROSCOPYf_plane_restr0.0041935

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