Protein-RNA and protein-protein recognition by dual KH1/2 domains of the neuronal splicing factor Nova-1

Marianna Teplova, Lucy Malinina, Jennifer C. Darnell, Jikui Song, Min Lu, Ruben Abagyan, Kiran Musunuru, Alexei Teplov, Stephen K. Burley, Robert B. Darnell, Dinshaw J. Patel

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Nova onconeural antigens are neuron-specific RNA-binding proteins implicated in paraneoplastic opsoclonus-myoclonus-ataxia (POMA) syndrome. Nova harbors three K-homology (KH) motifs implicated in alternate splicing regulation of genes involved in inhibitory synaptic transmission. We report the crystal structure of the first two KH domains (KH1/2) of Nova-1 bound to an in vitro selected RNA hairpin, containing a UCAG-UCAC high-affinity binding site. Sequence-specific intermolecular contacts in the complex involve KH1 and the second UCAC repeat, with the RNA scaffold buttressed by interactions between repeats. Whereas the canonical RNA-binding surface of KH2 in the above complex engages in protein-protein interactions in the crystalline state, the individual KH2 domain can sequence-specifically target the UCAC RNA element in solution. The observed antiparallel alignment of KH1 and KH2 domains in the crystal structure of the complex generates a scaffold that could facilitate target pre-mRNA looping on Nova binding, thereby potentially explaining Nova's functional role in splicing regulation.

Original languageEnglish (US)
Pages (from-to)930-944
Number of pages15
JournalStructure
Volume19
Issue number7
DOIs
StatePublished - Jul 13 2011

Bibliographical note

Funding Information:
D.J.P. received support from NIH grant CA49982, J.C.D. from NIH grant HD40647, R.B.D. from NIH grant NS34389, and K.M., S.K.B., and R.B.D. from NIH grant NS40955 and the Howard Hughes Medical Institute. K.M. received support from the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD program and NIH MSTP grant GM07739.

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