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- PDB-9wsr: Structure of mouse NLRP14-KDM2A-SKP1 complex -

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Basic information

Entry
Database: PDB / ID: 9wsr
TitleStructure of mouse NLRP14-KDM2A-SKP1 complex
Components
  • Lysine-specific demethylase 2A
  • NACHT, LRR and PYD domains-containing protein 14
  • S-phase kinase-associated protein 1
KeywordsCYTOSOLIC PROTEIN / Cryo-EM / Complex / early embryonic development / NLRP14 / KDM2A / SKP1 / ubiquitylation.
Function / homology
Function and homology information


Prolactin receptor signaling / [histone H3]-dimethyl-L-lysine36 demethylase / histone H3K36me/H3K36me2 demethylase activity / HDMs demethylate histones / SCF-beta-TrCP mediated degradation of Emi1 / Regulation of BACH1 activity / SCF(Skp2)-mediated degradation of p27/p21 / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Regulation of RUNX2 expression and activity ...Prolactin receptor signaling / [histone H3]-dimethyl-L-lysine36 demethylase / histone H3K36me/H3K36me2 demethylase activity / HDMs demethylate histones / SCF-beta-TrCP mediated degradation of Emi1 / Regulation of BACH1 activity / SCF(Skp2)-mediated degradation of p27/p21 / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Regulation of RUNX2 expression and activity / Degradation of GLI1 by the proteasome / Cyclin D associated events in G1 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Orc1 removal from chromatin / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Dectin-1 mediated noncanonical NF-kB signaling / NIK-->noncanonical NF-kB signaling / Degradation of beta-catenin by the destruction complex / Activation of NF-kappaB in B cells / Iron uptake and transport / FCERI mediated NF-kB activation / CLEC7A (Dectin-1) signaling / Interleukin-1 signaling / neuroepithelial cell differentiation / F-box domain binding / Downstream TCR signaling / histone H3K36 demethylase activity / GLI3 is processed to GLI3R by the proteasome / unmethylated CpG binding / PcG protein complex / Regulation of PLK1 Activity at G2/M Transition / : / Neddylation / gap junction / maintenance of protein location in nucleus / Cul7-RING ubiquitin ligase complex / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of epithelial cell apoptotic process / ubiquitin ligase activator activity / SCF ubiquitin ligase complex / heart looping / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin ligase complex scaffold activity / histone demethylase activity / cullin family protein binding / protein monoubiquitination / ubiquitin-like ligase-substrate adaptor activity / protein K48-linked ubiquitination / molecular function activator activity / transcription initiation-coupled chromatin remodeling / transcription coregulator activity / circadian regulation of gene expression / neural tube closure / regulation of circadian rhythm / beta-catenin binding / double-strand break repair via nonhomologous end joining / multicellular organism growth / neuron differentiation / protein polyubiquitination / regulation of inflammatory response / spermatogenesis / in utero embryonic development / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / cell differentiation / protein ubiquitination / chromatin remodeling / protein domain specific binding / negative regulation of gene expression / apoptotic process / positive regulation of gene expression / regulation of transcription by RNA polymerase II / centrosome / negative regulation of apoptotic process / chromatin / zinc ion binding / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
PHD-finger / Jumonji, helical domain / Jumonji helical domain / : / : / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain ...PHD-finger / Jumonji, helical domain / Jumonji helical domain / : / : / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / F-box-like / SKP1 component, dimerisation / S-phase kinase-associated protein 1 / SKP1-like, dimerisation domain superfamily / Skp1 family, dimerisation domain / F-box domain / Leucine rich repeat, ribonuclease inhibitor type / Leucine Rich repeat / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / Zinc finger, PHD-type, conserved site / Zinc finger PHD-type signature. / SKP1/BTB/POZ domain superfamily / Zinc finger PHD-type profile. / Leucine-rich repeat / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Leucine-rich repeat domain superfamily / Zinc finger, RING/FYVE/PHD-type / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Lysine-specific demethylase 2A / NACHT, LRR and PYD domains-containing protein 14 / S-phase kinase-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsLiu, S. / Jiao, H. / Yan, L. / Qi, Q. / Chi, P. / Lu, Y. / Li, J.H. / Li, J.L. / Ju, S. / Wang, X. ...Liu, S. / Jiao, H. / Yan, L. / Qi, Q. / Chi, P. / Lu, Y. / Li, J.H. / Li, J.L. / Ju, S. / Wang, X. / Hu, H. / Deng, D.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31971132 China
CitationJournal: Nat Commun / Year: 2026
Title: NLRP14 modulates the activity of E3 ubiquitin ligases during the oocyte-to-embryo transition.
Authors: Sibei Liu / Qianqian Qi / Pengliang Chi / Haizhan Jiao / Li Yan / Yuechao Lu / Rongrong Zhang / Jinhong Li / Sicheng Ju / Zhuo Han / Zihan Zhang / Qingting Liu / Guojin Ou / Jialu Li / Jing ...Authors: Sibei Liu / Qianqian Qi / Pengliang Chi / Haizhan Jiao / Li Yan / Yuechao Lu / Rongrong Zhang / Jinhong Li / Sicheng Ju / Zhuo Han / Zihan Zhang / Qingting Liu / Guojin Ou / Jialu Li / Jing Chen / Xiang Wang / Lei Li / Li Guo / Xue Jiao / Hongli Hu / Yongmei Jiang / Dong Deng /
Abstract: NLRP14 is an essential maternal factor for mammalian embryonic development. Maternal ablation of NLRP14 in mice impairs DNA demethylation and calcium homeostasis in zygotes, causing early embryonic ...NLRP14 is an essential maternal factor for mammalian embryonic development. Maternal ablation of NLRP14 in mice impairs DNA demethylation and calcium homeostasis in zygotes, causing early embryonic arrest. However, the underlying biochemical events remain largely unknown. Here, we identified two binding partners (KDM2A and UHRF1) of NLRP14 and further solved structures of NLRP14-KDM2A-SKP1 and NLRP14-UHRF1. Structural analysis revealed that NLRP14 modulates the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and the RING-type E3 ubiquitin ligase UHRF1 through two distinct mechanisms. Mechanistically, NLRP14 competitively inhibits KDM2A-mediated SCF assembly or allosterically inhibits the activity of UHRF1 by occupying the E2 ubiquitin-conjugating enzyme (UBE2D) binding site of the ubiquitin-like (UBL) domain. Deletion of NLRP14 in mice increases ubiquitination levels in oocytes during maturation and after fertilization. Collectively, our findings identify NLRP14 as a dual regulator that restrains E3 ubiquitin ligase-driven ubiquitination by limiting SCF complex assembly and attenuating UHRF1 activity. This regulatory role is required to prevent excessive protein ubiquitination and maintain proteostasis during the oocyte-to-embryo transition, thereby supporting early embryonic development. Our study uncovers maternal regulation of proteostasis in oocytes and suggests that dysregulating proteostasis is an important factor in the pathogenesis of reproductive disorders.
History
DepositionSep 15, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Lysine-specific demethylase 2A
C: S-phase kinase-associated protein 1
A: NACHT, LRR and PYD domains-containing protein 14


Theoretical massNumber of molelcules
Total (without water)176,5063
Polymers176,5063
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 Lysine-specific demethylase 2A / F-box and leucine-rich repeat protein 11 / F-box/LRR-repeat protein 11 / JmjC domain-containing ...F-box and leucine-rich repeat protein 11 / F-box/LRR-repeat protein 11 / JmjC domain-containing histone demethylation protein 1A / [Histone-H3]-lysine-36 demethylase 1A


Mass: 40626.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: KDM2A fused Strep tag at the N-terminal / Source: (gene. exp.) Mus musculus (house mouse) / Gene: Kdm2a, Fbl11, Fbxl11, Jhdm1a, Kiaa1004 / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: P59997, [histone H3]-dimethyl-L-lysine36 demethylase
#2: Protein S-phase kinase-associated protein 1 / Cyclin-A/CDK2-associated protein p19 / S-phase kinase-associated protein 1A / p19A / p19skp1


Mass: 20025.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: SKP1 fused Strep tag at the N-terminal / Source: (gene. exp.) Mus musculus (house mouse) / Gene: Skp1, Skp1a / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q9WTX5
#3: Protein NACHT, LRR and PYD domains-containing protein 14 / NALP-iota / Germ cell specific leucine-rich repeat NTPase


Mass: 115853.445 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: NLRP14 fused Flag tag at the N-terminal / Source: (gene. exp.) Mus musculus (house mouse) / Gene: Nlrp14, Nalp14 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q6B966
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: NLRP14-KDM2A-SKP1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameBuffer-ID
125 mMTris1
2150 mMNaCl1
32 mMDTT1
SpecimenConc.: 1.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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 magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 55.225 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 293321 / Symmetry type: POINT
RefinementCross valid method: NONE

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