Nucleic Acids Research Advance Access originally published online on June 24, 2009
Nucleic Acids Research 2009 37(15):5151-5166; doi:10.1093/nar/gkp546
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Nucleic Acids Research, 2009, Vol. 37, No. 15 5151-5166
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Structural basis for the sequence-specific RNA-recognition mechanism of human CUG-BP1 RRM3
1RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, 2Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 113-0033, 3Tatsuo Miyazawa Memorial Program, RIKEN Genomic Sciences Center, Yokohama 230-0045, Japan, 4Institute of Biophysical Chemistry and Frankfurt Institute of Advanced Studies, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany and 5Department of Biophysics and Biochemistry, Graduate School of Sciences, University of Tokyo, Tokyo 113-0033, Japan
*To whom correspondence should be addressed. Tel: +81 45 503 9196; Fax: +81 45 503 9195; Email: yokoyama{at}biochem.s.u-tokyo.ac.jp
Correspondence may also be addressed to Yutaka Muto. Tel: +81 45 503 9263; Fax: +81 45 503 9253; Email: ymuto{at}gsc.riken.jp
Received May 31, 2009. Revised June 9, 2009. Accepted June 10, 2009.
The CUG-binding protein 1 (CUG-BP1) is a member of the CUG-BP1 and ETR-like factors (CELF) family or the Bruno-like family and is involved in the control of splicing, translation and mRNA degradation. Several target RNA sequences of CUG-BP1 have been predicted, such as the CUG triplet repeat, the GU-rich sequences and the AU-rich element of nuclear pre-mRNAs and/or cytoplasmic mRNA. CUG-BP1 has three RNA-recognition motifs (RRMs), among which the third RRM (RRM3) can bind to the target RNAs on its own. In this study, we solved the solution structure of the CUG-BP1 RRM3 by hetero-nuclear NMR spectroscopy. The CUG-BP1 RRM3 exhibited a noncanonical RRM fold, with the four-stranded β-sheet surface tightly associated with the N-terminal extension. Furthermore, we determined the solution structure of the CUG-BP1 RRM3 in the complex with (UG)3 RNA, and discovered that the UGU trinucleotide is specifically recognized through extensive stacking interactions and hydrogen bonds within the pocket formed by the β-sheet surface and the N-terminal extension. This study revealed the unique mechanism that enables the CUG-BP1 RRM3 to discriminate the short RNA segment from other sequences, thus providing the molecular basis for the comprehension of the role of the RRM3s in the CELF/Bruno-like family.