Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 receptor reveals early phase molecular events during receptor activation

Aneesh Chandran,Xavier Chee,David L Prole,Taufiq Rahman

doi:10.1038/s41598-019-39301-3

Aneesh Chandran, Xavier Chee + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-39301-3

Copy DOI

Abstract

Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3 receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located ~100 Å away from the IP3-binding core (IBC). However, the precise mechanism of IP3 binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppressor domain (SD) and reveal correlated ‘clam closure’ dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD – IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3 binding that lead to channel gating.

Highlights

NT and establishes the suppressor domain (SD) to be critical for the conformational dynamics of IP3-binding core (IBC)
To elucidate the conformational dynamics associated with the activation of IP3 receptor (IP3R) by the natural agonist IP3, we performed all-atom unbiased molecular dynamics (MD) simulations of IP3R NT in its apo and IP3-bound states
root mean square deviation (RMSD) and root-mean-squared fluctuations (RMSFs) reflect the conformational changes at NT while IP3 binds, it is important to understand the prominent and collective domain motions associated with IP3 binding, which can provide insight into the IP3-mediated activation of IP3R

Summary

Introduction

NT and establishes the SD to be critical for the conformational dynamics of IBC. a tripartite interaction involving Glu283-Arg54-Asp[444] at the SD – IBC interface seemed critical for IP3R activation. Dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3 This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. IP3 rapidly diffuses into the cytosol and acts on IP3 receptors (IP3Rs) The latter represents a major class of intracellular Ca2+ channels, present primarily within the membrane of endoplasmic reticulum (ER). A recent 4.7 Å full length structure of rat IP3R1 solved through cryoelectron microscopy (cryo-EM)[6] shows that the IBC is located ~100 Å away from the pore region of the receptor. The cryo-EM structure of rat IP3R1 shows that, unlike the closely related ryanodine receptors (RyRs), the C-terminal tail of the IP3R directly interacts with the SD of NT and forms a connecting link between the pore-forming helices and the IP3-binding NT region. The IP3-dependent conformational changes are transmitted to the channel through the three large α-helical domains located between the NT and the transmembrane channel domain[7]

Objectives

Methods

Results

Conclusion