Document Detail


Structure of phosphorylated SF1 bound to U2AF⁶⁵ in an essential splicing factor complex.
MedLine Citation:
PMID:  23273425     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The essential splicing factors U2AF⁶⁵ and SF1 cooperatively bind consensus sequences at the 3' end of introns. Phosphorylation of SF1 on a highly conserved "SPSP" motif enhances its interaction with U2AF⁶⁵ and the pre-mRNA. Here, we reveal that phosphorylation induces essential conformational changes in SF1 and in the SF1/U2AF⁶⁵/3' splice site complex. Crystal structures of the phosphorylated (P)SF1 domain bound to the C-terminal domain of U2AF⁶⁵ at 2.29 Å resolution and of the unphosphorylated SF1 domain at 2.48 Å resolution demonstrate that phosphorylation induces a disorder-to-order transition within a previously unknown SF1/U2AF⁶⁵ interface. We find by small-angle X-ray scattering that the local folding of the SPSP motif transduces into global conformational changes in the nearly full-length (P)SF1/U2AF⁶⁵/3' splice site assembly. We further determine that SPSP phosphorylation and the SF1/U2AF⁶⁵ interface are essential in vivo. These results offer a structural prototype for phosphorylation-dependent control of pre-mRNA splicing factors.
Authors:
Wenhua Wang; Alexandre Maucuer; Ankit Gupta; Valérie Manceau; Karen R Thickman; William J Bauer; Scott D Kennedy; Joseph E Wedekind; Michael R Green; Clara L Kielkopf
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-12-27
Journal Detail:
Title:  Structure (London, England : 1993)     Volume:  21     ISSN:  1878-4186     ISO Abbreviation:  Structure     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-11     Completed Date:  2013-07-30     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  101087697     Medline TA:  Structure     Country:  United States    
Other Details:
Languages:  eng     Pagination:  197-208     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Ltd. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
PDB/4FXW;  4FXX
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Base Sequence
Cell Proliferation
Crystallography, X-Ray
DNA-Binding Proteins / chemistry*,  physiology
HEK293 Cells
HeLa Cells
Humans
Hydrogen Bonding
Mice
Models, Molecular
Molecular Sequence Data
NIH 3T3 Cells
Nuclear Proteins / chemistry*,  physiology
Phosphorylation
Protein Binding
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational*
Protein Structure, Quaternary
Protein Structure, Secondary
RNA Splice Sites
Ribonucleoproteins / chemistry*,  physiology
Transcription Factors / chemistry*,  physiology
Grant Support
ID/Acronym/Agency:
CA92584/CA/NCI NIH HHS; P01 CA092584/CA/NCI NIH HHS; P41 GM103485/GM/NIGMS NIH HHS; P41 RR001209/RR/NCRR NIH HHS; P41 RR001646/RR/NCRR NIH HHS; P41RR001209/RR/NCRR NIH HHS; R01 GM035490/GM/NIGMS NIH HHS; R01 GM035490/GM/NIGMS NIH HHS; R01 GM070503/GM/NIGMS NIH HHS; R01 GM070503/GM/NIGMS NIH HHS; RR01646/RR/NCRR NIH HHS; S10 RR026501/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/RNA Splice Sites; 0/Ribonucleoproteins; 0/SF1 protein, human; 0/Transcription Factors; 0/splicing factor U2AF
Comments/Corrections

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