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- EMDB-47265: CoREST complex bound to U2AF2 -

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Basic information

Entry
Database: EMDB / ID: EMD-47265
TitleCoREST complex bound to U2AF2
Map data
Sample
  • Complex: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1 and RCOR1
    • Protein or peptide: Lysine-specific histone demethylase 1A
    • Protein or peptide: REST corepressor 1
    • Protein or peptide: Splicing factor U2AF 65 kDa subunit
KeywordsRNA / splicing / melanoma / epigenetics / GENE REGULATION
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 / demethylase activity / FAD-dependent H3K4me/H3K4me3 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 / demethylase activity / FAD-dependent H3K4me/H3K4me3 demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development / neuron maturation / mRNA 3'-end processing / positive regulation of neural precursor cell proliferation / 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 / RNA Polymerase II Transcription Termination / negative regulation of DNA binding / 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 / Protein hydroxylation / negative regulation of DNA damage response, signal transduction by p53 class mediator / 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 ubiquitination / negative regulation of protein binding / mRNA Splicing - Major Pathway / : / positive regulation of RNA splicing / erythrocyte differentiation / positive regulation of protein ubiquitination / Regulation of PTEN gene transcription / epigenetic regulation of gene expression / promoter-specific chromatin binding / HDACs deacetylate histones / spliceosomal complex / negative regulation of DNA-binding transcription factor activity / cellular response to gamma radiation / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / 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 / chromatin organization / positive regulation of cold-induced thermogenesis / regulation of protein localization / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.14 Å
AuthorsHicks CW / Alani RM
Funding support United States, 1 items
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, 2024-
Header (metadata) releaseJan 8, 2025-
Map releaseJan 8, 2025-
UpdateJan 8, 2025-
Current statusJan 8, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47265.png

Downloads & links

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Map

FileDownload / File: emd_47265.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.9 Å/pix.
x 360 pix.
= 324. Å		0.9 Å/pix.
x 360 pix.
= 324. Å		0.9 Å/pix.
x 360 pix.
= 324. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.18983932 - 0.26469925
Average (Standard dev.)-0.00007972844 (±0.005987911)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47265_msk_1.map
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Half map: #2

Fileemd_47265_half_map_1.map
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Half map: #1

Fileemd_47265_half_map_2.map
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Sample components

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Entire : Splicing factor U2AF2 bound to the CoREST complex made up of LSD1...

EntireName: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1 and RCOR1
Components
  • Complex: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1 and RCOR1
    • Protein or peptide: Lysine-specific histone demethylase 1A
    • Protein or peptide: REST corepressor 1
    • Protein or peptide: Splicing factor U2AF 65 kDa subunit

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Supramolecule #1: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1...

SupramoleculeName: Splicing factor U2AF2 bound to the CoREST complex made up of LSD1 and RCOR1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Lysine-specific histone demethylase 1A

MacromoleculeName: Lysine-specific histone demethylase 1A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: Oxidoreductases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.126781 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: PSGVEGAAFQ SRLPHDRMTS QEAACFPDII SGPQQTQKVF LFIRNRTLQL WLDNPKIQLT FEATLQQLEA PYNSDTVLVH RVHSYLERH GLINFGIYKR IKPLPTKKTG KVIIIGSGVS GLAAARQLQS FGMDVTLLEA RDRVGGRVAT FRKGNYVADL G AMVVTGLG ...String:
PSGVEGAAFQ SRLPHDRMTS QEAACFPDII SGPQQTQKVF LFIRNRTLQL WLDNPKIQLT FEATLQQLEA PYNSDTVLVH RVHSYLERH GLINFGIYKR IKPLPTKKTG KVIIIGSGVS GLAAARQLQS FGMDVTLLEA RDRVGGRVAT FRKGNYVADL G AMVVTGLG GNPMAVVSKQ VNMELAKIKQ KCPLYEANGQ AVPKEKDEMV EQEFNRLLEA TSYLSHQLDF NVLNNKPVSL GQ ALEVVIQ LQEKHVKDEQ IEHWKKIVKT QEELKELLNK MVNLKEKIKE LHQQYKEASE VKPPRDITAE FLVKSKHRDL TAL CKEYDE LAETQGKLEE KLQELEANPP SDVYLSSRDR QILDWHFANL EFANATPLST LSLKHWDQDD DFEFTGSHLT VRNG YSCVP VALAEGLDIK LNTAVRQVRY TASGCEVIAV NTRSTSQTFI YKCDAVLCTL PLGVLKQQPP AVQFVPPLPE WKTSA VQRM GFGNLNKVVL CFDRVFWDPS VNLFGHVGST TASRGELFLF WNLYKAPILL ALVAGEAAGI MENISDDVIV GRCLAI LKG IFGSSAVPQP KETVVSRWRA DPWARGSYSY VAAGSSGNDY DLMAQPITPG PSIPGAPQPI PRLFFAGEHT IRNYPAT VH GALLSGLREA GRIADQFLGA MYTL

UniProtKB: Lysine-specific histone demethylase 1A

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Macromolecule #2: REST corepressor 1

MacromoleculeName: REST corepressor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.675833 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
RKPPKGMFLS QEDVEAVSAN ATAATTVLRQ LDMELVSVKR QIQNIKQTNS ALKEKLDGGI EPYRLPEVI

UniProtKB: REST corepressor 1

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Macromolecule #3: Splicing factor U2AF 65 kDa subunit

MacromoleculeName: Splicing factor U2AF 65 kDa subunit / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.64186 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SAHKLFIGGL PNYLNDDQVK ELLTSFGPLK AFNLVKDSAT GLSKGYAFCE YVDINVTDQA IAGLNGMQLG DKKLLVQRAS

UniProtKB: Splicing factor U2AF 65 kDa subunit

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 172429
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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