Article abstract
Nature Structural & Molecular Biology 14, 620 - 629 (2007)
Published online: 24 June 2007 | doi:10.1038/nsmb1260
There is an Erratum (August 2007) associated with this Article.
U2AF-homology motif interactions are required for alternative splicing regulation by SPF45
Lorenzo Corsini1,6, Sophie Bonnal2,6, Jerome Basquin1, Michael Hothorn1, Klaus Scheffzek1, Juan Valcárcel2 & Michael Sattler1,3,4,5
Abstract
The U2AF-homology motif (UHM) mediates protein-protein interactions between factors involved in constitutive RNA splicing. Here we report that the splicing factor SPF45 regulates alternative splicing of the apoptosis regulatory gene FAS (also called CD95). The SPF45 UHM is necessary for this activity and binds UHM-ligand motifs (ULMs) present in the 3' splice site–recognizing factors U2AF65, SF1 and SF3b155. We describe a 2.1-Å crystal structure of SPF45-UHM in complex with a ULM peptide from SF3b155. Features distinct from those of previously described UHM-ULM structures allowed the design of mutations in the SPF45 UHM that selectively impair binding to individual ULMs. Splicing assays using the ULM-selective SPF45 variants demonstrate that individual UHM-ULM interactions are required for FAS splicing regulation by SPF45 in vivo. Our data suggest that networks of UHM-ULM interactions are involved in regulating alternative splicing.
- European Molecular Biology Laboratory (EMBL), Meyerhofstr. 1, D-69117 Heidelberg, Germany.
- Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain.
- GSF-National Research Center for Environment and Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
- Munich Center for Integrated Protein Science, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
- Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
- These authors contributed equally to this work.
Correspondence to: Michael Sattler1,3,4,5 e-mail: sattler@embl.de
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