The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8

Ernesto Arias-Palomo, Akio Yamashita, Israel S. Fernández, Rafael Núñez-Ramírez, Yumi Bamba, Natsuko Izumi, Shigeo Ohno, Oscar Llorca

Research output: Contribution to journalArticle

Abstract

Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that regulates the degradation of mRNAs harboring premature translation termination codons. NMD also influences the expression of many physiological transcripts. SMG-1 is a large kinase essential to NMD that phosphorylates Upf1, which seems to be the definitive signal triggering mRNA decay. However, the regulation of the kinase activity of SMG-1 remains poorly understood. Here, we reveal the three-dimensional architecture of SMG-1 in complex with SMG-8 and SMG-9, and the structural mechanisms regulating SMG-1 kinase. A bent arm comprising a long region of HEAT (huntington, elongation factor 3, a subunit of PP2A and TOR1) repeats at the N terminus of SMG-1 functions as a scaffold for SMG-8 and SMG-9, and projects from the C-terminal core containing the phosphatidylinositol 3-kinase domain. SMG-9 seems to control the activity of SMG-1 indirectly through the recruitment of SMG-8 to the N-terminal HEAT repeat region of SMG-1. Notably, SMG-8 binding to the SMG-1:SMG-9 complex specifically down-regulates the kinase activity of SMG-1 on Upf1 without contacting the catalytic domain. Assembly of the SMG-1:SMG-8:SMG-9 complex induces a significant motion of the HEAT repeats that is signaled to the kinase domain. Thus, large-scale conformational changes induced by SMG-8 after SMG-9-mediated recruitment tune SMG-1 kinase activity to modulate NMD.

Original languageEnglish (US)
Pages (from-to)153-164
Number of pages12
JournalGenes and Development
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2011

Keywords

  • Cryo-EM
  • NMD
  • Nonsense-mediated mRNA decay
  • SMG-1
  • SMG-8
  • SMG-9

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Arias-Palomo, E., Yamashita, A., Fernández, I. S., Núñez-Ramírez, R., Bamba, Y., Izumi, N., Ohno, S., & Llorca, O. (2011). The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes and Development, 25(2), 153-164. https://doi.org/10.1101/gad.606911