InsP6 binding to PIKK kinases revealed by the cryo-EM structure of an SMG1-SMG8-SMG9 complex

Nat Struct Mol Biol. 2019 Dec;26(12):1089-1093. doi: 10.1038/s41594-019-0342-7. Epub 2019 Dec 2.

Abstract

We report the 3.45-Å resolution cryo-EM structure of human SMG1-SMG8-SMG9, a phosphatidylinositol-3-kinase (PI(3)K)-related protein kinase (PIKK) complex central to messenger RNA surveillance. Structural and MS analyses reveal the presence of inositol hexaphosphate (InsP6) in the SMG1 kinase. We show that the InsP6-binding site is conserved in mammalian target of rapamycin (mTOR) and potentially other PIKK members, and that it is required for optimal in vitro phosphorylation of both SMG1 and mTOR substrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Molecular
  • Phytic Acid / chemistry
  • Phytic Acid / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Protein Kinases / ultrastructure
  • Protein Multimerization
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Serine-Threonine Kinases / ultrastructure
  • RNA Stability

Substances

  • Intracellular Signaling Peptides and Proteins
  • SMG8 protein, human
  • SMG9 protein, human
  • Phytic Acid
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • SMG1 protein, human