HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA

Sci Rep. 2013 Oct 14:3:2931. doi: 10.1038/srep02931.

Abstract

CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF(65) and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Case-Control Studies
  • Cell Line
  • Exons
  • Gene Expression Regulation*
  • Gene Order
  • Heterogeneous-Nuclear Ribonucleoprotein L / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Molecular Sequence Data
  • Motor Endplate / pathology
  • Motor Endplate / physiopathology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation
  • Myasthenic Syndromes, Congenital / genetics
  • Myasthenic Syndromes, Congenital / metabolism
  • Nucleotide Motifs
  • Polypyrimidine Tract-Binding Protein / metabolism*
  • Proline-Rich Protein Domains
  • Protein Binding
  • RNA Precursors / genetics*
  • RNA Precursors / metabolism
  • RNA Splicing*
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / genetics*
  • Receptors, Nicotinic / metabolism
  • Regulatory Sequences, Nucleic Acid

Substances

  • CHRNA1 protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein L
  • RNA Precursors
  • Receptors, Nicotinic
  • Polypyrimidine Tract-Binding Protein