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

Longfei Wang, Yunsun Nam, Anna K. Lee, Chunxiao Yu, Kira Roth, Casandra Chen, Elizabeth M. Ransey, Piotr Sliz

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2664-2675
Number of pages12
JournalCell Reports
Volume18
Issue number11
DOIs
StatePublished - Mar 14 2017

Keywords

  • LIN28
  • LIN28A
  • RNA binding protein
  • RNA degradation
  • TUT4
  • TUTase
  • X-ray structure
  • Zcchc11
  • let-7
  • oligouridylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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