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- PDB-9dwu: CoREST complex bound to U2AF2 -

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Basic information

Entry
Database: PDB / ID: 9dwu
TitleCoREST complex bound to U2AF2
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
  • Splicing factor U2AF 65 kDa subunit
KeywordsGENE REGULATION / RNA / splicing / melanoma / epigenetics
Function / homology
Function and homology information


U2AF complex / poly-pyrimidine tract binding / pre-mRNA 3'-splice site binding / positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity ...U2AF complex / poly-pyrimidine tract binding / pre-mRNA 3'-splice site binding / positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development / positive regulation of neural precursor cell proliferation / mRNA 3'-end processing / C2H2 zinc finger domain binding / MRF binding / regulation of androgen receptor signaling pathway / commitment complex / Transport of Mature mRNA derived from an Intron-Containing Transcript / DNA repair complex / negative regulation of DNA binding / RNA Polymerase II Transcription Termination / U2-type prespliceosome / molecular function inhibitor activity / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of neuroblast proliferation / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / spliceosomal complex assembly / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / Protein hydroxylation / negative regulation of mRNA splicing, via spliceosome / histone deacetylase complex / histone demethylase activity / positive regulation of cell size / positive regulation of epithelial to mesenchymal transition / response to fungicide / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to cAMP / transcription repressor complex / negative regulation of protein binding / negative regulation of protein ubiquitination / mRNA Splicing - Major Pathway / erythrocyte differentiation / positive regulation of RNA splicing / epigenetic regulation of gene expression / Regulation of PTEN gene transcription / positive regulation of protein ubiquitination / HDACs deacetylate histones / negative regulation of DNA-binding transcription factor activity / spliceosomal complex / promoter-specific chromatin binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / cellular response to gamma radiation / mRNA splicing, via spliceosome / cerebral cortex development / positive regulation of neuron projection development / mRNA processing / transcription corepressor activity / cellular response to UV / p53 binding / flavin adenine dinucleotide binding / regulation of protein localization / chromatin organization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / transcription regulator complex / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / transcription coactivator activity / chromosome, telomeric region / oxidoreductase activity / nuclear speck / negative regulation of gene expression / negative regulation of DNA-templated transcription / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
U2 snRNP auxilliary factor, large subunit, splicing factor / : / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / SWIRM domain ...U2 snRNP auxilliary factor, large subunit, splicing factor / : / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / SANT domain profile. / Amine oxidase / Flavin containing amine oxidoreductase / SANT domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Lysine-specific histone demethylase 1A / Splicing factor U2AF 65 kDa subunit / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.14 Å
AuthorsHicks, C.W. / Alani, R.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private#1045461 United States
CitationJournal: bioRxiv / Year: 2024
Title: CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity.
Authors: Robert J Fisher / Kihyun Park / Kwangwoon Lee / Katarina Pinjusic / Allison Vanasse / Christina S Ennis / Scott Ficcaro / Jarrod Marto / Stephanie Stransky / Joseph Duke-Cohan / Anupa ...Authors: Robert J Fisher / Kihyun Park / Kwangwoon Lee / Katarina Pinjusic / Allison Vanasse / Christina S Ennis / Scott Ficcaro / Jarrod Marto / Stephanie Stransky / Joseph Duke-Cohan / Anupa Geethadevi / Eric Raabe / Simone Sidoli / Chad W Hicks / Derin B Keskin / Catherine J Wu / Philip A Cole / Rhoda M Alani
Abstract: Epigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique interactions ...Epigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex with RNA splicing factors and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex inhibitor, corin, leading to extensive changes in RNA splicing in melanoma and other malignancies. Using predictive machine learning models and MHC IP-MS, we identify thousands of corin-induced neopeptides derived from unannotated splice sites which generate immunogenic splice-neoantigens. Furthermore, corin reactivates the response to immune checkpoint blockade and promotes dramatic expansion of cytotoxic T cells in an immune cold melanoma model. CoREST complex inhibition thus represents a unique therapeutic opportunity in cancer which creates tumor-associated neoantigens that enhance the immunogenicity of current therapeutics.
STATEMENT OF SIGNIFICANCE: We identify a novel role of the CoREST transcriptional repressor complex in regulating pre-mRNA splicing and find that the small molecule inhibitor, corin, promotes ...STATEMENT OF SIGNIFICANCE: We identify a novel role of the CoREST transcriptional repressor complex in regulating pre-mRNA splicing and find that the small molecule inhibitor, corin, promotes alternative splicing events in cancer leading to neoantigen expression and T cell-mediated immunity. This represents a potential approach to promote immunoreactive neoantigen expression in immune-cold tumors.
History
DepositionOct 10, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 8, 2025Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Lysine-specific histone demethylase 1A
B: REST corepressor 1
C: Splicing factor U2AF 65 kDa subunit


Theoretical massNumber of molelcules
Total (without water)90,4443
Polymers90,4443
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 histone demethylase 1A / BRAF35-HDAC complex protein BHC110 / Flavin-containing amine oxidase domain-containing protein 2


Mass: 74126.781 Da / Num. of mol.: 1 / Fragment: UNP residues 171-836
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM1A, AOF2, KDM1, KIAA0601, LSD1 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: O60341, Oxidoreductases
#2: Protein REST corepressor 1 / Protein CoREST


Mass: 7675.833 Da / Num. of mol.: 1 / Fragment: UNP residues 311-379
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RCOR1, KIAA0071, RCOR / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q9UKL0
#3: Protein Splicing factor U2AF 65 kDa subunit / U2 auxiliary factor 65 kDa subunit / hU2AF(65) / hU2AF65 / U2 snRNP auxiliary factor large subunit


Mass: 8641.860 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: U2AF2, U2AF65 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P26368
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: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1 and RCOR1
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293F
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 172429 / Symmetry type: POINT

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