The Signature of the Five-Stranded vRRM Fold Defined by Functional, Structural and Computational Analysis of the hnRNP L Protein. Issue 19 (25th September 2015)

• Record Type: Journal Article
• Authors: Blatter, Markus; Dunin-Horkawicz, Stanislaw; Grishina, Inna; Maris, Christophe; Thore, Stephane; Maier, Timm; Bindereif, Albrecht; Bujnicki, Janusz M.; Allain, Frédéric H.-T.
• Is Part Of: Journal of molecular biology. Volume 427:Issue 19(2015:Oct. 01)
• Page Start: 3001
• Page End: 3022
• Publication Date: 2015-09-25
• Subjects: RRM RNA recognition motif -- hnRNP L heterogeneous nuclear ribonucleoprotein L -- ICC interacting C-terminal coil -- RBP RNA binding protein -- hnRNP LL heterogeneous nuclear ribonucleoprotein L-like -- HSQC heteronuclear single quantum coherence -- IRC interacting RRM consensus -- HMM hidden Markov model -- GST glutathione S-transferase -- EDTA ethylenediaminetetraacetic acid -- TROSY transverse relaxation optimized spectroscopy -- NOESY nuclear Overhauser enhancement spectroscopy -- SLS Swiss Light Source; hnRNP L -- RNA recognition motif -- hnRNP L -- repressor function -- interacting C-terminal coil -- fifth β-strand -- evolutionary analysis; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2015.05.020
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: The RNA recognition motif (RRM) is the far most abundant RNA binding domain. In addition to the typical β1 α1 β2 β3 α2 β4 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. Graphical abstract: Highlights: Structure–function relationship in hnRNP L and PTB paralog families. Domain requirement of hnRNP L in repressing exon 4 of SLC2A2 . Molecular signatures underlying ICCs and the five-stranded vRRM fold. Phylogenetic clustering of the new families and evolutionary scenario of vRRMs. Presented analysis provides concepts to classify abundant RRM fold extensions.