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Discovery and characterization of autoinhibition in the S. pombe decapping complex

  • Author(s): Paquette, David Russell
  • Advisor(s): Gross, John D
  • et al.
Abstract

The decapping complex is a dynamic enzyme that is involved in dynamic processes of development and environment stress responses. In vivo, and to some extent in vitro, decapping has been shown to be modulated by numerous cellular cofactors; including Dhh1 and Pat1:Lsm1-7, which help define the timing of decapping. Additional coactivating sequences contained in lineage specific proteins allow for plasticity in recruiting the complex to novel pathways. Recently, great progress has been made in describing the structured, core domains of the various 5’ decay factors and the decapping structure has been solved in multiple forms that represent various conformations along its enzymatic trajectory; including coactivator bound. Much less is known about the intrinsically disorder regions (IDRs) of these proteins. In vivo results have implicated that there could be a negative regulatory element in the decapping complex. Following this insight, I have discovered and subsequently characterized an autoinhibitory region of the fungal Dcp2 IDR. Additionally, this autoinhibitory complex reveals a potentially larger role for Edc3 in cytoplasmic decay that had previously been unappreciated. This autoinhibition provides new possibilities for our understanding of mRNA decay and this system provides the opportunity to resolve differences between in vivo and in vitro decapping results. Finally, our biochemical and structural insights into the core Dcp1:Dcp2 activation have resulted in an enzyme that may prove useful for RNA cloning methods.

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