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Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins

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Author(s)

  • Katherine S Bridge
  • Kunal M Shah
  • Yigen Li
  • Daniel E Foxler
  • Sybil C K Wong
  • Duncan C Miller
  • Kathryn M Davidson
  • John G Foster
  • Ruth Rose
  • Michael R Hodgkinson
  • Paulo S Ribeiro
  • A Aziz Aboobaker
  • Kenta Yashiro
  • Xiaozhong Wang
  • Paul R Graves
  • Michael J Plevin
  • Dimitris Lagos
  • Tyson V Sharp

Department/unit(s)

Publication details

JournalCell reports
DateAccepted/In press - 9 Jun 2017
DatePublished (current) - 5 Jul 2017
Issue number1
Volume20
Number of pages15
Pages (from-to)173-187
Original languageEnglish

Abstract

As core components of the microRNA-induced silencing complex (miRISC), Argonaute (AGO) proteins interact with TNRC6 proteins, recruiting other effectors of translational repression/mRNA destabilization. Here, we show that LIMD1 coordinates the assembly of an AGO-TNRC6 containing miRISC complex by binding both proteins simultaneously at distinct interfaces. Phosphorylation of AGO2 at Ser 387 by Akt3 induces LIMD1 binding, which in turn enables AGO2 to interact with TNRC6A and downstream effector DDX6. Conservation of this serine in AGO1 and 4 indicates this mechanism may be a fundamental requirement for AGO function and miRISC assembly. Upon CRISPR-Cas9-mediated knockout of LIMD1, AGO2 miRNA-silencing function is lost and miRNA silencing becomes dependent on a complex formed by AGO3 and the LIMD1 family member WTIP. The switch to AGO3 utilization occurs due to the presence of a glutamic acid residue (E390) on the interaction interface, which allows AGO3 to bind to LIMD1, AJUBA, and WTIP irrespective of Akt signaling.

Bibliographical note

© 2017, The Author(s).

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  • Journal Article

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