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 & development
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2011
Externally publishedYes

Fingerprint

Nonsense Mediated mRNA Decay
Phosphotransferases
RNA Stability
Phosphatidylinositol 3-Kinase
Peptide Elongation Factors
Terminal Repeat Sequences
Nonsense Codon
Catalytic Domain
Down-Regulation

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

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

The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. / Arias-Palomo, Ernesto; Yamashita, Akio; Fernández, Israel S.; Núñez-Ramírez, Rafael; Bamba, Yumi; Izumi, Natsuko; Ohno, Shigeo; Llorca, Oscar.

In: Genes & development, Vol. 25, No. 2, 15.01.2011, p. 153-164.

Research output: Contribution to journalArticle

Arias-Palomo, E, Yamashita, A, Fernández, IS, 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 & development, vol. 25, no. 2, pp. 153-164. https://doi.org/10.1101/gad.606911
Arias-Palomo E, Yamashita A, Fernández IS, Núñez-Ramírez R, Bamba Y, Izumi N et al. The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes & development. 2011 Jan 15;25(2):153-164. https://doi.org/10.1101/gad.606911
Arias-Palomo, Ernesto ; Yamashita, Akio ; Fernández, Israel S. ; Núñez-Ramírez, Rafael ; Bamba, Yumi ; Izumi, Natsuko ; Ohno, Shigeo ; Llorca, Oscar. / The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. In: Genes & development. 2011 ; Vol. 25, No. 2. pp. 153-164.
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