Journal
NUCLEIC ACIDS RESEARCH
Volume 32, Issue 16, Pages 4852-4861Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkh799
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS034389, R01NS040955] Funding Source: NIH RePORTER
- NIGMS NIH HHS [GM07739, T32 GM007739] Funding Source: Medline
- NINDS NIH HHS [R01 NS034389, R01 NS040955, R56 NS034389, NS34389] Funding Source: Medline
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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.
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