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- PDB-9k1y: Structure of the SF3B core, harboring the R625H mutation in SF3B1... -

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Basic information

Entry
Database: PDB / ID: 9k1y
TitleStructure of the SF3B core, harboring the R625H mutation in SF3B1, in complex with intron-U2 snRNA
Components
  • (Splicing factor 3B subunit ...) x 3
  • PHD finger-like domain-containing protein 5A
  • U2 snRNA
  • pre-mRNA intron
KeywordsSPLICING/RNA / mRNA splicing / hotspot mutation / SPLICING-RNA complex
Function / homology
Function and homology information


U11/U12 snRNP / B-WICH complex / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / splicing factor binding / U2-type precatalytic spliceosome / U2-type spliceosomal complex / U2-type prespliceosome assembly / SAGA complex / U2 snRNP ...U11/U12 snRNP / B-WICH complex / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / splicing factor binding / U2-type precatalytic spliceosome / U2-type spliceosomal complex / U2-type prespliceosome assembly / SAGA complex / U2 snRNP / U2-type prespliceosome / positive regulation of transcription by RNA polymerase III / precatalytic spliceosome / spliceosomal complex assembly / positive regulation of transcription by RNA polymerase I / regulation of RNA splicing / mRNA Splicing - Minor Pathway / U2 snRNA binding / regulation of DNA repair / catalytic step 2 spliceosome / mRNA Splicing - Major Pathway / RNA splicing / stem cell differentiation / spliceosomal complex / mRNA splicing, via spliceosome / negative regulation of protein catabolic process / B-WICH complex positively regulates rRNA expression / nuclear matrix / nuclear speck / chromatin remodeling / mRNA binding / positive regulation of DNA-templated transcription / protein-containing complex binding / nucleolus / positive regulation of transcription by RNA polymerase II / DNA binding / RNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Splicing factor 3B, subunit 5 / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 1 / PHF5-like / PHF5-like protein / Splicing factor 3B subunit 5/RDS3 complex subunit 10 / Splicing factor 3B subunit 10 (SF3b10) / Splicing factor 3B subunit 1-like / : / PPP2R1A-like HEAT repeat ...Splicing factor 3B, subunit 5 / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 1 / PHF5-like / PHF5-like protein / Splicing factor 3B subunit 5/RDS3 complex subunit 10 / Splicing factor 3B subunit 10 (SF3b10) / Splicing factor 3B subunit 1-like / : / PPP2R1A-like HEAT repeat / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / Armadillo-like helical / Armadillo-type fold / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
RNA / RNA (> 10) / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 3 / PHD finger-like domain-containing protein 5A / Splicing factor 3B subunit 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsZhang, Y. / Yin, C. / Huang, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nucleic Acids Res / Year: 2025
Title: A common structural mechanism for RNA recognition by the SF3B complex in mRNA splicing and export.
Authors: Yuzhu Zhang / Changping Yin / Yimin Wang / Kunming Yan / Bo Zhao / Xin Hu / Youzhong Wan / Hong Cheng / Jing Huang /
Abstract: The SF3B complex plays a critical role in branch point adenosine recognition during pre-mRNA splicing. Its largest subunit SF3B1 is frequently mutated in cancers, leading to aberrant alternative ...The SF3B complex plays a critical role in branch point adenosine recognition during pre-mRNA splicing. Its largest subunit SF3B1 is frequently mutated in cancers, leading to aberrant alternative splicing. Besides its function in pre-mRNA splicing, the SF3B complex also binds mature or intronless mRNAs to facilitate their nuclear export. Notably, the RNA motifs recognized by the SF3B complex exhibit no apparent sequence similarities, raising the question of how the SF3B complex recognizes diverse mRNA sequences for various cellular activities. Here we report the cryo-EM structures of the human SF3B complex associated with either intronless histone mRNAs or intron-U2 snRNA. These structures unveil that both mRNA molecules adopt a similar conformation featuring a bulged adenosine and bind the SF3B complex in a remarkably resembling manner, suggesting that SF3B recognizes the specific shape rather than the sequence of its RNA targets. Further cryo-EM and molecular dynamics analyses of the hotspot-mutant SF3B complexes bound to intron-U2 snRNA demonstrate that the SF3B1K700E and SF3B1R625H mutations similarly repel the attachment of the intronic polypyrimidine tract around the mutation sites, leading to reduced RNA-binding affinity. Altogether, our study provides structural insights into the RNA-recognition mechanism of the SF3B complex and suggests that the cancer-associated SF3B1 mutations could potentially affect multiple cellular processes including mRNA splicing and export, which advances our understanding of the pathogenic mechanisms of the SF3B1 mutations.
History
DepositionOct 16, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Splicing factor 3B subunit 1
D: PHD finger-like domain-containing protein 5A
A: Splicing factor 3B subunit 3
B: Splicing factor 3B subunit 5
G: pre-mRNA intron
H: U2 snRNA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)277,0499
Polymers276,8536
Non-polymers1963
Water00
1


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

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Components

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Splicing factor 3B subunit ... , 3 types, 3 molecules CAB

#1: Protein Splicing factor 3B subunit 1 / Pre-mRNA-splicing factor SF3b 155 kDa subunit / SF3b155 / Spliceosome-associated protein 155 / SAP 155


Mass: 101173.633 Da / Num. of mol.: 1 / Mutation: R625H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SF3B1, SAP155 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O75533
#3: Protein Splicing factor 3B subunit 3 / Pre-mRNA-splicing factor SF3b 130 kDa subunit / SF3b130 / STAF130 / Spliceosome-associated protein ...Pre-mRNA-splicing factor SF3b 130 kDa subunit / SF3b130 / STAF130 / Spliceosome-associated protein 130 / SAP 130


Mass: 136678.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SF3B3, KIAA0017, SAP130 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q15393
#4: Protein Splicing factor 3B subunit 5 / SF3b5 / Pre-mRNA-splicing factor SF3b 10 kDa subunit


Mass: 10149.369 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SF3B5, SF3B10 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BWJ5

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RNA chain , 2 types, 2 molecules GH

#5: RNA chain pre-mRNA intron


Mass: 10718.358 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: in vitro transcription vector pT7-TP(deltai) (others)
#6: RNA chain U2 snRNA


Mass: 5705.339 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: in vitro transcription vector pT7-TP(deltai) (others)

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Protein / Non-polymers , 2 types, 4 molecules D

#2: Protein PHD finger-like domain-containing protein 5A / PHD finger-like domain protein 5A / Splicing factor 3B-associated 14 kDa protein / SF3b14b


Mass: 12427.524 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHF5A / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q7RTV0
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
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: SF3B core with R625H mutation in SF3B1 complexed with intron-U2 snRNA
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 3000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71636 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00218171
ELECTRON MICROSCOPYf_angle_d0.52624795
ELECTRON MICROSCOPYf_dihedral_angle_d8.1732786
ELECTRON MICROSCOPYf_chiral_restr0.0422849
ELECTRON MICROSCOPYf_plane_restr0.0043058

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