期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：38
页码：E3966-E3975
DOI：10.1073/pnas.1409730111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceReversible and repetitive structural changes are essential for ligand-gated ion channels to mediate biological signaling. The inositol 1,4,5-trisphosphate receptor (IP3R) assembles ligand-gated ion channels that mediate calcium signaling. IP3 activates channels at a distance by reversible allosteric changes in the IP3R tetramer. Here we show a new mode of posttranslational modification that irreversibly blocks allosteric changes in the IP3R. We identified an IP3R-modifying enzyme as tissue transglutaminase that inhibits IP3R function by locking subunit configurations. This modification chronically impaired calcium signaling and autophagy regulation in living cells, and up-regulated modification was observed in Huntington disease models. To our knowledge, this is the first demonstration of transglutaminase-catalyzed posttranslational modification in ligand-gated channel allostery and provides a new framework for enzymatic regulation of allostery. 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.
