Structural dynamics underlying gating and regulation in IP₃R channel

Abstract

Inositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca2+ and ATP in IP3R1, revealing conformational changes that couple ligand-binding to channel opening. Using a deep learning approach, we extracted dynamic properties of the key protein domains. From this, we find that IP3 binding relies upon intrinsic flexibility of the cytoplasmic ARM2 domain. Our results highlight a key role of dynamic side chains surrounding the ion conduction path in regulating gating behavior of IP3R channels. Altogether, this work defines a structural platform for mechanistic understanding of the molecular dynamics underlying ligand-binding, activation and regulation of the IP3R activity.

Using mass spectrometry imaging to visualize age-related subcellular disruption

“…Skeletal muscle responds to a continuum of stressors that challenge metabolic homeostasis and either forge an adaptive change or result in pathogenesis. Evidence is mounting in support of a role for contact sites between mitochondria and the sarcoplasmic reticulum (SR), a specialized form of ER charged with Ca 2+ storage, Ca 2+ (Mikoshiba, 2015;Bartok et al, 2019;Fan et al, 2022;Schmitz et al, 2022). An additional MAMenriched protein called SEPN1 has been identified at the ER/SR interface (Filipe et al, 2021).…”