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Evidence for cooperative tandem binding of hnRNP C RRMs in mRNA processing.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2015
Author Cieniková Zuzana, Jayne Sandrine, Damberger Fred Franz, Allain Frédéric Hai-Trieu, Maris Christophe,
Project NMR structure determination of protein-RNA complexes involved in pre-mRNA splicing and translation regulation
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Original article (peer-reviewed)

Journal RNA (New York, N.Y.)
Volume (Issue) 21(11)
Page(s) 1931 - 42
Title of proceedings RNA (New York, N.Y.)
DOI 10.1261/rna.052373.115


The human hnRNP C is a ubiquitous cellular protein involved in mRNA maturation. Recently, we have shown that this protein specifically recognizes uridine (U) pentamers through its single RNA recognition motif (RRM). However, a large fraction of natural RNA targets of hnRNP C consists of much longer contiguous uridine stretches. To understand how these extended sites are recognized, we studied the binding of the RRM to U-tracts of 8-11 bases. In vivo investigation of internal translation activation of unr (upstream of N-ras) mRNA indicates that the conservation of the entire hnRNP C binding site, UC(U)8, is required for hnRNP C-dependent IRES activation. The assays further suggest a synergistic interplay between hnRNP C monomers, dependent on the protein's ability to oligomerize. In vitro spectroscopic and thermodynamic analyses show that isolated RRMs bind to (U)11 oligomers as dimers. Structural modeling of a ternary double-RRM/RNA complex indicates additionally that two RRM copies can be accommodated on the canonical sequence UC(U)8. The proposed tandem RRM binding is in very good agreement with the transcriptome-wide recognition of extended U-tracts by full-length hnRNP C, which displays a cross-linking pattern consistent with a positively cooperative RRM dimer binding model.