Determination and augmentation of RNA sequence specificity of the Nova K-homology domains

Nucleic Acids Research
K Musunuru, R B Darnell

Abstract

The Nova onconeural antigens are implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus-ataxia (POMA). The Nova antigens are neuron-specific RNA-binding proteins harboring three repeats of the K-homology (KH) motif; they have been implicated in the regulation of alternative splicing of a host of genes involved in inhibitory synaptic transmission. Although the third Nova KH domain (KH3) has been extensively characterized using biochemical and crystallographic techniques, the roles of the KH1 and KH2 domains remain unclear. Furthermore, the specificity determinants that distinguish the Nova KH domains from those of the closely related hnRNP E and hnRNP K proteins are undefined. We demonstrate through the use of RNA selection and biochemical analysis that the sequence specificity of the Nova KH1/2 domains is similar to that of Nova KH3. We also show that the mutagenesis of a Nova KH domain to render it similar to the KH domains of the heterogeneous nuclear ribonucleoprotein E (hnRNP E) and hnRNP K allow it to recognize longer RNA sequences. These data yield important insights into KH domain function and suggest a strategy by which to engineer KH domains with novel sequence preferences.

References

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Citations

Mar 27, 2007·Cold Spring Harbor Symposia on Quantitative Biology·R B Darnell
Aug 16, 2005·Genes, Brain, and Behavior·J C DarnellR B Darnell
Aug 15, 2012·Molecular and Cellular Biology·Jamie PurcellJ Andrew Berglund
Jan 10, 2008·Nephron. Experimental Nephrology·Denise J BouvretteElizabeth C Bryda
Jan 15, 2011·RNA·Crystal L Young, Katrin Karbstein
Mar 8, 2008·Behavioural Brain Research·Kiven E Lukong, Stéphane Richard
Feb 8, 2008·Current Opinion in Structural Biology·Alexander Serganov, Dinshaw J Patel
Mar 19, 2016·Wiley Interdisciplinary Reviews. RNA·Lama Darbelli, Stéphane Richard
Feb 2, 2006·Analytical Biochemistry·Chengjian MaoDavid J Shapiro
Jul 4, 2015·Neuron·Viachaslau Bernat, Matthew D Disney
Dec 17, 2008·Human Molecular Genetics·Marie RogneThomas Küntziger
Jul 28, 2007·Journal of the American Chemical Society·Barbara BeuthAndres Ramos

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