Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

• Published in: Nature structural & molecular biology Vol. 19; no. 12; pp. 1282 - 1286
• Main Authors: Nicastro, Giuseppe, García-Mayoral, María Flor, Hollingworth, David, Kelly, Geoff, Martin, Stephen R, Briata, Paola, Gherzi, Roberto, Ramos, Andres
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2012; Nature Publishing Group
• Subjects: 631/337/1645; 631/337/384/331; 631/45/535; Analysis; Biochemistry; Biological Microscopy; Biosynthesis; Caenorhabditis elegans; Cellular biology; Gene expression; Genetic aspects; Humans; Life Sciences; Membrane Biology; MicroRNA; MicroRNAs - biosynthesis; Models, Molecular; Molecular structure; Nuclear Magnetic Resonance, Biomolecular; Oncology; Physiological aspects; Protein binding; Protein Structure; Proteins; Ribonucleic acid; RNA; RNA-Binding Proteins - physiology; Structure; Trans-Activators - physiology; United Kingdom
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2427

The protein KSRP binds to precursors of let-7 miRNA and promotes their processing to the mature form. The molecular basis for KSRP's specificity for pre-let-7 is now examined by using NMR spectroscopy and biochemistry, which reveals that the third KH domain of KSRP recognizes a G-rich sequence in the pre-let-7 terminal loop in a noncanonical manner. Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP–let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre–let-7 terminal loop and dominates the interaction. The structure of the KH3–RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor.