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.
journal_name
Proc Natl Acad Sci U S Aauthors
Hamada K,Terauchi A,Nakamura K,Higo T,Nukina N,Matsumoto N,Hisatsune C,Nakamura T,Mikoshiba Kdoi
10.1073/pnas.1409730111subject
Has Abstractpub_date
2014-09-23 00:00:00pages
E3966-75issue
38eissn
0027-8424issn
1091-6490pii
1409730111journal_volume
111pub_type
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