Reports

Structure of PTB Bound to RNA: Specific Binding and Implications for Splicing Regulation

Florian C. Oberstrass,^1,4* Sigrid D. Auweter,^1,4* Michèle Erat,^1* Yann Hargous,¹ Anke Henning,¹ Philipp Wenter,³ Luc Reymond,³ Batoul Amir-Ahmady,² Stefan Pitsch,³ Douglas L. Black,² Frédéric H.-T. Allain¹

The polypyrimidine tract binding protein (PTB) is a 58-kilodalton RNA binding protein involved in multiple aspects of messenger RNA metabolism, including the repression of alternative exons. We have determined the solution structures of the four RNA binding domains (RBDs) of PTB, each bound to a CUCUCU oligonucleotide. Each RBD binds RNA with a different binding specificity. RBD3 and RBD4 interact, resulting in an antiparallel orientation of their bound RNAs. Thus, PTB will induce RNA looping when bound to two separated pyrimidine tracts within the same RNA. This leads to structural models for how PTB functions as an alternative-splicing repressor.

¹ Institute for Molecular Biology and Biophysics, Department of Biology, Swiss Federal Institute of Technology, Zürich, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
² Department of Microbiology, Immunology, and Molecular Genetics and Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Laboratory of Nucleic Acid Chemistry LCAN-EPFL, Lausanne, Switzerland.
⁴ Molecular Life Science Ph.D. Program, Zürich, Switzerland.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: allain{at}mol.biol.ethz.ch

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A Polypyrimidine Tract-Binding Protein-Dependent Pathway of mRNA Stability Initiates with CpG Activation of Primary B Cells.

J. F. Porter, S. Vavassori, and L. R. Covey (2008)
J. Immunol. 181, 3336-3345
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Bioinformatic and functional analysis of RNA secondary structure elements among different genera of human and animal caliciviruses.

P. Simmonds, I. Karakasiliotis, D. Bailey, Y. Chaudhry, D. J. Evans, and I. G. Goodfellow (2008)
Nucleic Acids Res. 36, 2530-2546
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The third RNA recognition motif of Drosophila ELAV protein has a role in multimerization.

G. Toba and K. White (2008)
Nucleic Acids Res. 36, 1390-1399
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Regulation of Neuron-Specific Alternative Splicing of Neurofibromatosis Type 1 Pre-mRNA.

H. Zhu, M. N. Hinman, R. A. Hasman, P. Mehta, and H. Lou (2008)
Mol. Cell. Biol. 28, 1240-1251
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Does distance matter? Variations in alternative 3' splicing regulation.

M. Akerman and Y. Mandel-Gutfreund (2007)
Nucleic Acids Res.
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Repression of {alpha}-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract.

A. J. Matlin, J. Southby, C. Gooding, and C. W.J. Smith (2007)
RNA 13, 1214-1223
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PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation.

G. C. Coutinho-Mansfield, Y. Xue, Y. Zhang, and X.-D. Fu (2007)
Genes & Dev. 21, 1573-1577
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A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.

P. L. Boutz, P. Stoilov, Q. Li, C.-H. Lin, G. Chawla, K. Ostrow, L. Shiue, M. Ares Jr., and D. L. Black (2007)
Genes & Dev. 21, 1636-1652
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Polypyrimidine Tract Binding Protein 2 Stabilizes Phosphoglycerate Kinase 2 mRNA in Murine Male Germ Cells by Binding to Its 3'UTR.

M. Xu and N. B. Hecht (2007)
Biol Reprod 76, 1025-1033
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A U-turn motif-containing stem-loop in the coronavirus 5' untranslated region plays a functional role in replication.

P. Liu, L. Li, J. J. Millership, H. Kang, J. L. Leibowitz, and D. P. Giedroc (2007)
RNA 13, 763-780
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The Polypyrimidine Tract Binding Protein (PTB) Represses Splicing of Exon 6B from the {beta}-Tropomyosin Pre-mRNA by Directly Interfering with the Binding of the U2AF65 Subunit.

J. Sauliere, A. Sureau, A. Expert-Bezancon, and J. Marie (2006)
Mol. Cell. Biol. 26, 8755-8769
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Sequence-specific binding of single-stranded RNA: is there a code for recognition?.

S. D. Auweter, F. C. Oberstrass, and F. H.-T. Allain (2006)
Nucleic Acids Res. 34, 4943-4959
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NMR structure of the three quasi RNA recognition motifs (qRRMs) of human hnRNP F and interaction studies with Bcl-x G-tract RNA: a novel mode of RNA recognition.

C. Dominguez and F. H.-T. Allain (2006)
Nucleic Acids Res. 34, 3634-3645
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Short, synthetic and selectively 13C-labeled RNA sequences for the NMR structure determination of protein-RNA complexes.

P. Wenter, L. Reymond, S. D. Auweter, F. H.-T. Allain, and S. Pitsch (2006)
Nucleic Acids Res. 34, e79
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Characterization of multimeric complexes formed by the human PTB1 protein on RNA.

C. CLERTE and K. B. HALL (2006)
RNA 12, 457-475
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A Splicing Repressor Domain in Polypyrimidine Tract-binding Protein.

F. Robinson and C. W. J. Smith (2006)
J. Biol. Chem. 281, 800-806
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RNA-Binding Domain Proteins in Kinetoplastids: a Comparative Analysis.

J. De Gaudenzi, A. C. Frasch, and C. Clayton (2005)
Eukaryot. Cell 4, 2106-2114
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