LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Longfei Wang, Yunsun Nam, Anna K. Lee, Chunxiao Yu, Kira Roth, Casandra Chen, Elizabeth M. Ransey, Piotr Sliz
LIN28 is an RNA binding protein that plays crucial roles in pluripotency, glucose metabolism, tissue regeneration, and tumorigenesis. LIN28 binds to the let-7 primary and precursor microRNAs through bipartite recognition and induces degradation of let-7 precursors (pre-let-7) by promoting oligouridylation by terminal uridylyltransferases (TUTases). Here, we report that the zinc knuckle domain (ZKD) of mouse LIN28 recruits TUT4 to initiate the oligouridylation of let-7 precursors. Our crystal structure of human LIN28 in complex with a fragment of pre-let-7f-1 determined to 2.0 Å resolution shows that the interaction between ZKD and RNA is constrained to a small cavity with a high druggability score. We demonstrate that the specific interaction between ZKD and pre-let-7 is necessary and sufficient to induce oligouridylation by recruiting the N-terminal fragment of TUT4 (NTUT4) and the formation of a stable ZKD:NTUT4:pre-let-7 ternary complex is crucial for the acquired processivity of TUT4.

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Teaser

LIN28 initiates degradation of let-7 precursors by recruiting terminal uridylyltransferases (TUTases), TUT4 and TUT7, to oligouridylate the let-7 RNA. Wang et al. describe how LIN28, TUT4, and let-7 precursors form a ternary complex and carry out the oligouridylation activity.


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