Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist.

Azumaya CM, Linton EA, Risener CJ, Nakagawa T, Karakas E
J Biol Chem. 2020 295 (6): 1743-1753

PMID: 31915246 · PMCID: PMC7008357 · DOI:10.1074/jbc.RA119.011570

Calcium-mediated signaling through inositol 1,4,5-triphosphate receptors (IPRs) is essential for the regulation of numerous physiological processes, including fertilization, muscle contraction, apoptosis, secretion, and synaptic plasticity. Deregulation of IPRs leads to pathological calcium signaling and is implicated in many common diseases, including cancer and neurodegenerative, autoimmune, and metabolic diseases. Revealing the mechanism of activation and inhibition of this ion channel will be critical to an improved understanding of the biological processes that are controlled by IPRs. Here, we report structural findings of the human type-3 IPR (IPR-3) obtained by cryo-EM (at an overall resolution of 3.8 Å), revealing an unanticipated regulatory mechanism where a loop distantly located in the primary sequence occupies the IP-binding site and competitively inhibits IP binding. We propose that this inhibitory mechanism must differ qualitatively among IPR subtypes because of their diverse loop sequences, potentially serving as a key molecular determinant of subtype-specific calcium signaling in IPRs. In summary, our structural characterization of human IPR-3 provides critical insights into the mechanistic function of IPRs and into subtype-specific regulation of these important calcium-regulatory channels.

© 2020 Azumaya et al.

MeSH Terms (9)

Binding Sites Calcium Signaling Cryoelectron Microscopy Humans Inositol 1,4,5-Trisphosphate Inositol 1,4,5-Trisphosphate Receptors Models, Molecular Peptides Protein Conformation

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