Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E3966-75. doi: 10.1073/pnas.1409730111. Epub 2014 Sep 8.

Abstract

The inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum mediates calcium signaling that impinges on intracellular processes. IP3Rs are allosteric proteins comprising four subunits that form an ion channel activated by binding of IP3 at a distance. Defective allostery in IP3R is considered crucial to cellular dysfunction, but the specific mechanism remains unknown. Here we demonstrate that a pleiotropic enzyme transglutaminase type 2 targets the allosteric coupling domain of IP3R type 1 (IP3R1) and negatively regulates IP3R1-mediated calcium signaling and autophagy by locking the subunit configurations. The control point of this regulation is the covalent posttranslational modification of the Gln2746 residue that transglutaminase type 2 tethers to the adjacent subunit. Modification of Gln2746 and IP3R1 function was observed in Huntington disease models, suggesting a pathological role of this modification in the neurodegenerative disease. Our study reveals that cellular signaling is regulated by a new mode of posttranslational modification that chronically and enzymatically blocks allosteric changes in the ligand-gated channels that relate to disease states.

Keywords: IP3 receptor; allosteric regulation; deamidation; isopeptide bond; transamidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / genetics
  • Animals
  • Autophagy*
  • Calcium Signaling*
  • Disease Models, Animal
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • PC12 Cells
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary
  • Rats
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Itpr1 protein, rat
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins