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- PDB-9nwe: E3 ligase UBR4-KCMF1-calmodulin complex -

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Basic information

Entry
Database: PDB / ID: 9nwe
TitleE3 ligase UBR4-KCMF1-calmodulin complex
Components
  • Calmodulin-1
  • E3 ubiquitin-protein ligase KCMF1
  • E3 ubiquitin-protein ligase UBR4
KeywordsLIGASE / E3 ligase / UBR4 / ISR
Function / homology
Function and homology information


negative regulation of HRI-mediated signaling / synaptic signaling / ubiquitin-dependent protein catabolic process via the N-end rule pathway / protein K27-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / negative regulation of fatty acid biosynthetic process / endosome organization / cytoplasm protein quality control / protein K11-linked ubiquitination ...negative regulation of HRI-mediated signaling / synaptic signaling / ubiquitin-dependent protein catabolic process via the N-end rule pathway / protein K27-linked ubiquitination / cytoplasm protein quality control by the ubiquitin-proteasome system / protein branched polyubiquitination / negative regulation of fatty acid biosynthetic process / endosome organization / cytoplasm protein quality control / protein K11-linked ubiquitination / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / positive regulation of ryanodine-sensitive calcium-release channel activity / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / organelle localization by membrane tethering / negative regulation of ryanodine-sensitive calcium-release channel activity / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / tertiary granule membrane / ficolin-1-rich granule membrane / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / protein K63-linked ubiquitination / catalytic complex / Smooth Muscle Contraction / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / protein K48-linked ubiquitination / calcium channel inhibitor activity / specific granule membrane / cellular response to interferon-beta / presynaptic cytosol / Protein methylation / Activation of AMPK downstream of NMDARs / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / sperm midpiece / voltage-gated potassium channel complex / regulation of calcium-mediated signaling / calcium channel complex / positive regulation of autophagy / substantia nigra development / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / FCGR3A-mediated IL10 synthesis / adenylate cyclase activator activity / calyx of Held / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / protein serine/threonine kinase activator activity / VEGFR2 mediated cell proliferation / sarcomere / regulation of cytokinesis / VEGFR2 mediated vascular permeability / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / positive regulation of receptor signaling pathway via JAK-STAT / RAF activation / Transcriptional activation of mitochondrial biogenesis / RING-type E3 ubiquitin transferase / Stimuli-sensing channels / cellular response to type II interferon / long-term synaptic potentiation / response to calcium ion / RAS processing / spindle pole / Signaling by RAF1 mutants
Similarity search - Function
E3 ubiquitin-protein ligase UBR4, N-terminal / : / : / E3 ubiquitin-protein ligase UBR4 N-terminal / E3 ubiquitin-protein ligase UBR4-like domain / Drought induced 19 protein type, zinc-binding domain / Drought induced 19 protein (Di19), zinc-binding / E3 ubiquitin ligase UBR4, C-terminal / E3 ubiquitin ligase UBR4-like / E3 ubiquitin-protein ligase UBR4 ...E3 ubiquitin-protein ligase UBR4, N-terminal / : / : / E3 ubiquitin-protein ligase UBR4 N-terminal / E3 ubiquitin-protein ligase UBR4-like domain / Drought induced 19 protein type, zinc-binding domain / Drought induced 19 protein (Di19), zinc-binding / E3 ubiquitin ligase UBR4, C-terminal / E3 ubiquitin ligase UBR4-like / E3 ubiquitin-protein ligase UBR4 / UBR4 E3 catalytic module profile. / : / Putative zinc finger in N-recognin (UBR box) / Zinc finger, UBR-type / Zinc finger UBR-type profile. / Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway / Zinc finger ZZ-type signature. / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / Zinc finger, ZZ type / Zinc finger, ZZ-type / Zinc finger, ZZ-type superfamily / Zinc finger ZZ-type profile. / zinc finger / : / Zinc finger C2H2 type domain profile. / Zinc finger C2H2-type / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Armadillo-type fold / WD40-repeat-containing domain superfamily
Similarity search - Domain/homology
Calmodulin-1 / E3 ubiquitin-protein ligase UBR4 / E3 ubiquitin-protein ligase KCMF1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYang, Z. / Rape, M.P.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
The G. Harold and Leila Y. Mathers Foundation United States
Citation
Journal: Nature / Year: 2025
Title: Molecular basis of SIFI activity in the integrated stress response.
Authors: Zhi Yang / Diane L Haakonsen / Michael Heider / Samuel R Witus / Alex Zelter / Tobias Beschauner / Michael J MacCoss / Michael Rapé /
Abstract: Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor ...Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor of the integrated stress response (SIFI), to terminate stress response signalling and ensure cellular homeostasis. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here we combine cryo-electron microscopy analysis of endogenous SIFI with AlphaFold modelling and biochemical studies to report the structural and mechanistic basis of the silencing of the integrated stress response. SIFI detects both stress indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and therefore allows a single enzyme to monitor and, if needed, modulate a complex cellular state.
#1: Journal: Biorxiv / Year: 2024
Title: The molecular basis of integrated stress response silencing
Authors: Yang, Z. / Haakonsen, D.L. / Heider, M. / Witus, S.R. / Zelter, A. / Beschauner, T. / MacCoss, M.J. / Rape, M.
History
DepositionMar 22, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase UBR4
B: E3 ubiquitin-protein ligase UBR4
C: Calmodulin-1
D: Calmodulin-1
E: E3 ubiquitin-protein ligase KCMF1
F: E3 ubiquitin-protein ligase KCMF1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,272,60416
Polymers1,272,0526
Non-polymers55310
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein E3 ubiquitin-protein ligase UBR4 / 600 kDa retinoblastoma protein-associated factor / p600 / N-recognin-4 / Retinoblastoma-associated ...600 kDa retinoblastoma protein-associated factor / p600 / N-recognin-4 / Retinoblastoma-associated factor of 600 kDa / RBAF600


Mass: 577180.938 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: HEK293T
References: UniProt: Q5T4S7, RING-type E3 ubiquitin transferase
#2: Protein Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P0DP23
#3: Protein E3 ubiquitin-protein ligase KCMF1 / FGF-induced in gastric cancer / Potassium channel modulatory factor / PCMF / ZZ-type zinc finger- ...FGF-induced in gastric cancer / Potassium channel modulatory factor / PCMF / ZZ-type zinc finger-containing protein 1


Mass: 41992.348 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
References: UniProt: Q9P0J7, RING-type E3 ubiquitin transferase
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestN
Has protein modificationY

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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: Human E3 ubiquitin ligase UBR4-KCMF1-calmodulin complex (Silencing Factor of ISR, SiFI)
Type: COMPLEX / Entity ID: #1-#3 / Source: NATURAL
Molecular weightValue: 1.27 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 3.6 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: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 87263 / Symmetry type: POINT

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