Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28

Fionna E. Loughlin, Luca F R Gebert, Harry Towbin, Andreas Brunschweiger, Jonathan Hall, Frédéric H T Allain

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83 Citations (Scopus)


Lin28 inhibits the biogenesis of let-7 miRNAs through a direct interaction with the terminal loop of pre-let-7. This interaction requires the zinc-knuckle domains of Lin28. We show that the zinc knuckle domains of Lin28 are sufficient to provide binding selectivity for pre-let-7 miRNAs and present the NMR structure of human Lin28 zinc knuckles bound to the short sequence 5′-AGGAGAU-3′. The structure reveals that each zinc knuckle recognizes an AG dinucleotide separated by a single nucleotide spacer. This defines a new 5′-NGNNG-3′ consensus motif that explains how Lin28 selectively recognizes pre-let-7 family members. Binding assays in cell lysates and functional assays in cultured cells demonstrate that the interactions observed in the solution structure also occur between the full-length protein and members of the pre-let-7 family. The consensus sequence explains several seemingly disparate previously published observations on the binding properties of Lin28.

Original languageEnglish
Pages (from-to)84-91
Number of pages8
JournalNature Structural & Molecular Biology
Issue number1
Publication statusPublished - Jan 2012
Externally publishedYes

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