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Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD

Roberto Melero1, Akiko Uchiyama2, Raquel Castaño1

  • 1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (Spanish National Research Council), Ramiro de Maeztu 9, 28040 Madrid, Spain.

Structure (London, England : 1993)
|July 9, 2014
PubMed

Insights

The SMG1C complex regulates nonsense-mediated mRNA decay (NMD) by binding UPF1 and UPF2. This interaction facilitates UPF2 transfer, inducing conformational changes to activate UPF1 and initiate NMD.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial surveillance pathway for maintaining transcriptome integrity.
  • SMG1, a PI3K-related kinase, is essential for NMD initiation through UPF1 phosphorylation.
  • The precise mechanism of SMG1 and UPF1 activation by UPF2 remains incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory mechanism of SMG1 kinase activity by UPF2 during NMD.
  • To determine the structural basis for the interaction between SMG1C, UPF1, and UPF2.

Main Methods:

  • Cryo-electron microscopy to determine the structure of SMG1C-UPFs complexes.
  • In vivo and in vitro interaction analyses.
  • Competition experiments and site-directed mutagenesis.

Main Results:

  • SMG1C recruits UPF1 and UPF2 to distinct sites near the kinase domain.
  • UPF2 binds SMG1 independently of UPF1, recognizing the FRB domain.
  • UPF2 can be transferred to UPF1 within SMG1C, inducing activating conformational changes in UPF1.

Conclusions:

  • The SMG1C-UPF2 interaction is a key regulatory step in NMD.
  • UPF2 acts as a bridge, transferring between SMG1C and UPF1 to facilitate UPF1 activation.
  • This study reveals a novel mechanism for kinase activation in the NMD pathway.

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