Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control

作者：Danilenko Marina; Dalgliesh Caroline; Pagliarini Vittoria; Naro Chiara; Ehrmann Ingrid; Feracci Mikael; Kheirollahi Chadegani Mahsa; Tyson Capper Alison; Clowry Gavin J; Fort Philippe; Dominguez Cyril; Sette Claudio; Elliott David J^*

来源：Nucleic Acids Research, 2017, 45(7): 4120-4130.

DOI：10.1093/nar/gkw1277

SLM2 and Sam68 are splicing regulator paralogs that usually overlap in function, yet only SLM2 and not Sam68 controls the Neurexin2 AS4 exon important for brain function. Herein we find that SLM2 and Sam68 similarly bind to Neurexin2 premRNA, both within the mouse cortex and in vitro. Protein domainswap experiments identify a region including the STAR domain that differentiates SLM2 and Sam68 activity in splicing target selection, and confirm that this is not established via the variant amino acids involved in RNA contact. However, far fewer SLM2 and Sam68 RNA binding sites flank the Neurexin2 AS4 exon, compared with those flanking the Neurexin1 and Neurexin3 AS4 exons under joint control by both Sam68 and SLM2. Doubling binding site numbers switched paralog sensitivity, by placing the Neurexin2 AS4 exon under joint splicing control by both Sam68 and SLM2. Our data support a model where the density of shared RNA binding sites around a target exon, rather than different paralog-specific proteinRNA binding sites, controls functional target specificity between SLM2 and Sam68 on the Neurexin2 AS4 exon. Similar models might explain differential control by other splicing regulators within families of paralogs with indistinguishable RNA binding sites.

• 出版日期2017-4-20
• 单位河北医科大学