title: Molecular basis for interaction of let-7 microRNAs with Lin28.
abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene expression. Among these, members of the let-7 miRNA family control many cell-fate determination genes to influence pluripotency, differentiation, and transformation. Lin28 is a specific, posttranscriptional inhibitor of let-7 biogenesis. We report crystal structures of mouse Lin28 in complex with sequences from let-7d, let-7-f1, and let-7 g precursors. The two folded domains of Lin28 recognize two distinct regions of the RNA and are sufficient for inhibition of let-7 in vivo. We also show by NMR spectroscopy that the linker connecting the two folded domains is flexible, accommodating Lin28 binding to diverse let-7 family members. Protein-RNA complex formation imposes specific conformations on both components that could affect downstream recognition by other processing factors. Our data provide a molecular explanation for Lin28 specificity and a model for how it regulates let-7.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yunsun
authors.initials: Y
authors.lastname: Nam
authors.forename: Casandra
authors.initials: C
authors.lastname: Chen
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
authors.forename: James J
authors.initials: JJ
authors.lastname: Chou
authors.forename: Piotr
authors.initials: P
authors.lastname: Sliz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse
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