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Role of Dimerization in KH/RNA Complexes:  The Example of Nova KH3

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    Role of Dimerization in KH/RNA Complexes:  The Example of Nova KH3
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    NIMR, The Ridgeway, London NW7 1AA, United Kingdom
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    Biochemistry

    Cite this: Biochemistry 2002, 41, 13, 4193–4201
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    https://doi.org/10.1021/bi011994o
    Published March 9, 2002
    Copyright © 2002 American Chemical Society
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    Abstract

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    The K homology module, one of the most common RNA-binding motifs, is present in multiple copies in both prokaryotic and eukaryotic regulatory proteins. Increasing evidence suggests that self-aggregation of KH modules has a functional role. We have used a combination of techniques to characterize the behavior in solution of the third KH domain of Nova-1, a paradigmatic KH protein. The possibility of working on the isolated module allowed us to observe specifically the homodimerization and RNA-binding properties of KH domains. We provide conclusive evidence that self-association of Nova-1 KH3 occurs in solution even in the absence of RNA. Homodimerization involves a specific protein/protein interface. We also studied the dynamical behavior of Nova-1 KH3 in isolation and in complex with RNA. These data provide a model for the mechanism of KH/RNA recognition and suggest functional implications of dimerization in KH complexes. We discuss our findings in the context of the whole KH family and suggest a generalized mode of interaction.

    Copyright © 2002 American Chemical Society

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    T1, T2, and NOEs for Nova-1 KH1. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 32 publications.

    1. Barbara Beuth,, María Flor García-Mayoral,, Ian A. Taylor, and, Andres Ramos. Scaffold-Independent Analysis of RNA−Protein Interactions:  The Nova-1 KH3−RNA Complex. Journal of the American Chemical Society 2007, 129 (33) , 10205-10210. https://doi.org/10.1021/ja072365q
    2. Marie Rogne,, Helga B. Landsverk,, Aleyde Van Eynde,, Monique Beullens,, Mathieu Bollen,, Philippe Collas, and, Thomas Küntziger. The KH-Tudor Domain of A-Kinase Anchoring Protein 149 Mediates RNA-Dependent Self-Association. Biochemistry 2006, 45 (50) , 14980-14989. https://doi.org/10.1021/bi061418y
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    10. David Hollingworth, Adela M. Candel, Giuseppe Nicastro, Stephen R. Martin, Paola Briata, Roberto Gherzi, Andres Ramos. KH domains with impaired nucleic acid binding as a tool for functional analysis. Nucleic Acids Research 2012, 40 (14) , 6873-6886. https://doi.org/10.1093/nar/gks368
    11. Juke Wang, Mengyuan Xu, Kai Zhu, Lei Li, Xinqi Liu, . The N-terminus of FILIA Forms an Atypical KH Domain with a Unique Extension Involved in Interaction with RNA. PLoS ONE 2012, 7 (1) , e30209. https://doi.org/10.1371/journal.pone.0030209
    12. Cyprian D. Cukier, Andres Ramos. Modular protein-RNA interactions regulating mRNA metabolism: a role for NMR. European Biophysics Journal 2011, 40 (12) , 1317-1325. https://doi.org/10.1007/s00249-011-0698-z
    13. Congli Cai, Keiko Tamai, Kathleen Molyneaux, . KHDC1B Is a Novel CPEB Binding Partner Specifically Expressed in Mouse Oocytes and Early Embryos. Molecular Biology of the Cell 2010, 21 (18) , 3137-3148. https://doi.org/10.1091/mbc.e10-03-0255
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    20. Roberto Valverde, Irina Pozdnyakova, Tommi Kajander, Janani Venkatraman, Lynne Regan. Fragile X Mental Retardation Syndrome: Structure of the KH1-KH2 Domains of Fragile X Mental Retardation Protein. Structure 2007, 15 (9) , 1090-1098. https://doi.org/10.1016/j.str.2007.06.022
    21. Bradley M. Lunde, Claire Moore, Gabriele Varani. RNA-binding proteins: modular design for efficient function. Nature Reviews Molecular Cell Biology 2007, 8 (6) , 479-490. https://doi.org/10.1038/nrm2178
    22. María Flor García-Mayoral, David Hollingworth, Laura Masino, Irene Díaz-Moreno, Geoff Kelly, Roberto Gherzi, Chu-Fang Chou, Ching-Yi Chen, Andres Ramos. The Structure of the C-Terminal KH Domains of KSRP Reveals a Noncanonical Motif Important for mRNA Degradation. Structure 2007, 15 (4) , 485-498. https://doi.org/10.1016/j.str.2007.03.006
    23. Jernej Ule, Robert B. Darnell. Functional and Mechanistic Insights From Genome-Wide Studies of Splicing Regulation in the Brain. 2007, 148-160. https://doi.org/10.1007/978-0-387-77374-2_9
    24. C.-P. Benny Yiu, Rebecca L. Beavil, H.Y. Edwin Chan. Biophysical characterisation reveals structural disorder in the nucleolar protein, Dribble. Biochemical and Biophysical Research Communications 2006, 343 (1) , 311-318. https://doi.org/10.1016/j.bbrc.2006.02.153
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    27. Zhihua Du, John K. Lee, Richard Tjhen, Shang Li, Hu Pan, Robert M. Stroud, Thomas L. James. Crystal Structure of the First KH Domain of Human Poly(C)-binding Protein-2 in Complex with a C-rich Strand of Human Telomeric DNA at 1.7 Å. Journal of Biological Chemistry 2005, 280 (46) , 38823-38830. https://doi.org/10.1074/jbc.M508183200
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    29. R. Andrew Atkinson, Bruno Kieffer. The role of protein motions in molecular recognition: insights from heteronuclear NMR relaxation measurements. Progress in Nuclear Magnetic Resonance Spectroscopy 2004, 44 (3-4) , 141-187. https://doi.org/10.1016/j.pnmrs.2004.01.001
    30. Sean P Ryder, Leah A Frater, Dana L Abramovitz, Elizabeth B Goodwin, James R Williamson. RNA target specificity of the STAR/GSG domain post-transcriptional regulatory protein GLD-1. Nature Structural & Molecular Biology 2004, 11 (1) , 20-28. https://doi.org/10.1038/nsmb706
    31. B. Kate Dredge, Robert B. Darnell. Nova Regulates GABA A Receptor γ2 Alternative Splicing via a Distal Downstream UCAU-Rich Intronic Splicing Enhancer. Molecular and Cellular Biology 2003, 23 (13) , 4687-4700. https://doi.org/10.1128/MCB.23.13.4687-4700.2003
    32. ANDRES RAMOS, DAVID HOLLINGWORTH, ANNALISA PASTORE. The role of a clinically important mutation in the fold and RNA-binding properties of KH motifs. RNA 2003, 9 (3) , 293-298. https://doi.org/10.1261/rna.2168503
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    Biochemistry

    Cite this: Biochemistry 2002, 41, 13, 4193–4201
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi011994o
    Published March 9, 2002
    Copyright © 2002 American Chemical Society
    Request reuse permissions

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