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Crystallographic analysis of polypyrimidine tract-binding protein-Raver1 interactions involved in regulation of alternative splicing.

ABSTRACT: The polypyrimidine tract-binding protein (PTB) is an important regulator of alternative splicing. PTB-regulated splicing of ?-tropomyosin is enhanced by Raver1, a protein with four PTB-Raver1 interacting motifs (PRIs) that bind to the helical face of the second RNA recognition motif (RRM2) in PTB. We present the crystal structures of RRM2 in complex with PRI3 and PRI4 from Raver1, which--along with structure-based mutagenesis--reveal the molecular basis of their differential binding. High-affinity binding by Raver1 PRI3 involves shape-matched apolar contacts complemented by specific hydrogen bonds, a new variant of an established mode of peptide-RRM interaction. Our results refine the sequence of the PRI motif and place important structural constraints on functional models of PTB-Raver1 interactions. Our analysis indicates that the observed Raver1-PTB interaction is a general mode of binding that applies to Raver1 complexes with PTB paralogues such as nPTB and to complexes of Raver2 with PTB.

SUBMITTER: Joshi A

PROVIDER: S-EPMC3420021 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Crystallographic analysis of polypyrimidine tract-binding protein-Raver1 interactions involved in regulation of alternative splicing.

Joshi Amar A Coelho Miguel B MB Kotik-Kogan Olga O Simpson Peter J PJ Matthews Stephen J SJ Smith Christopher W J CW Curry Stephen S

Structure (London, England : 1993) 20111201 12

The polypyrimidine tract-binding protein (PTB) is an important regulator of alternative splicing. PTB-regulated splicing of α-tropomyosin is enhanced by Raver1, a protein with four PTB-Raver1 interacting motifs (PRIs) that bind to the helical face of the second RNA recognition motif (RRM2) in PTB. We present the crystal structures of RRM2 in complex with PRI3 and PRI4 from Raver1, which--along with structure-based mutagenesis--reveal the molecular basis of their differential binding. High-affini ...[more]

PMID: 22153504

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Project description:Alternative splicing (AS) generates transcript variants by the definition of different exonic and intronic regions and causes a massive expansion of transcriptome diversity. Changes in AS patterns have been found to be linked to manifold biological processes, yet fundamental aspects such as the regulation of AS and the functional implications of altered AS programs largely remain to be addressed. In this work, widespread AS regulation by Arabidopsis Polypyrimidine tract-binding protein homologues (AtPTBs) was revealed. In total 452 AS events derived from 308 distinct genes were found to be responsive to the levels of the splicing factors AtPTB1 and AtPTB2, which predominantly triggered splicing of regulated introns, inclusion of cassette exons, and usage of upstream 5' splice sites. In contrast, alternative 3' splice site events were strongly underrepresented among the AtPTB1/2 targets and no major AS regulatory function of the distantly related AtPTB3 was found. Dependent on their position within the mRNA, AtPTB-regulated events can both modify the untranslated regions and give rise to alternative protein products. Gene ontology analysis revealed a connection of AtPTB-mediated AS control with diverse biological processes, and the functional implications of selected AS events were further elucidated in the context of seed germination and flowering time control. Specifically, AtPTB misexpression changes AS of the PHYTOCHROME INTERACTING FACTOR 6 (PIF6) pre-mRNA, coinciding with altered rates of abscisic acid-dependent seed germination. Furthermore, AS patterns as well as the expression of key flowering regulators were massively changed in an AtPTB1/2 level-dependent manner. In conclusion, our work has revealed widespread AS regulatory functions of the AtPTB splicing factors with important functional implications in various fundamental processes of Arabidopsis development. Analysis of alternative splicing patterns in plants with increased and decreased levels of the 3 Arabidopsis Polypyrimidine-tract binding protein homologues in comparison to wild type samples, determined in duplicates

Dataset Information

Crystallographic analysis of polypyrimidine tract-binding protein-Raver1 interactions involved in regulation of alternative splicing.

Publications

Crystallographic analysis of polypyrimidine tract-binding protein-Raver1 interactions involved in regulation of alternative splicing.

Similar Datasets

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