Non-canonical Guanine recognition mediates KSRP regulation of Let-7 biogenesis

Let-7 is an important tumor-suppressive microRNA 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 cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP-pre-Let-7 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 non-canonical 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.