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

Vittoria Pagliarini, Claudio Sette, Marina Danilenko, Caroline Dalgliesh, Chiara Naro, Ingrid Ehrmann, Mikael Feracci, Mahsa Kheirollahi-Chadegani, Alison Tyson-Capper, Gavin J. Clowry, Philippe Fort, Cyril Dominguez, David J. Elliott

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

6 Citazioni (Scopus)

Abstract

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 pre-mRNA, both within the mouse cortex and in vitro. Protein domain-swap 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 protein-RNA 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.
Lingua originaleEnglish
pagine (da-a)4120-4130
Numero di pagine11
RivistaNucleic Acids Research
Volume45
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Adaptor Proteins, Signal Transducing
  • Alternative Splicing
  • Animals
  • Binding Sites
  • Exons
  • Genetics
  • Introns
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Protein Domains
  • RNA Precursors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Substrate Specificity

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