The Signature of the Five-Stranded vRRM Fold Defined by Functional, Structural and Computational Analysis of the hnRNP L Protein

J Mol Biol. 2015 Sep 25;427(19):3001-22. doi: 10.1016/j.jmb.2015.05.020. Epub 2015 Jun 5.


The RNA recognition motif (RRM) is the far most abundant RNA binding domain. In addition to the typical β1α1β2β3α2β4 fold, various sub-structural elements have been described and reportedly contribute to the high functional versatility of RRMs. The heterogeneous nuclear ribonucleoprotein L (hnRNP L) is a highly abundant protein of 64 kDa comprising four RRM domains. Involved in many aspects of RNA metabolism, hnRNP L specifically binds to RNAs containing CA repeats or CA-rich clusters. However, a comprehensive structural description of hnRNP L including its sub-structural elements is missing. Here, we present the structural characterization of the RRM domains of hnRNP L and demonstrate their function in repressing exon 4 of SLC2A2. By comparison of the sub-structural elements between the two highly similar paralog families of hnRNP L and PTB, we defined signatures underlying interacting C-terminal coils (ICCs), the RRM34 domain interaction and RRMs with a C-terminal fifth β-strand, a variation we denoted vRRMs. Furthermore, computational analysis revealed new putative ICC-containing RRM families and allowed us to propose an evolutionary scenario explaining the origins of the ICC and fifth β-strand sub-structural extensions. Our studies provide insights of domain requirements in alternative splicing mediated by hnRNP L and molecular descriptions for the sub-structural elements. In addition, the analysis presented may help to classify other abundant RRM extensions and to predict structure-function relationships.

Keywords: RNA recognition motif; evolutionary analysis; fifth β-strand; hnRNP L; interacting C-terminal coil; repressor function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Exons*
  • Glucose Transporter Type 2 / genetics*
  • Heterogeneous-Nuclear Ribonucleoprotein L / chemistry*
  • Heterogeneous-Nuclear Ribonucleoprotein L / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Phylogeny
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA / genetics
  • RNA / metabolism*


  • Glucose Transporter Type 2
  • Heterogeneous-Nuclear Ribonucleoprotein L
  • RNA