Structural characterization of inositol triphosphate receptors
EMSL Project ID
51197
Abstract
The overall goal of the research studies proposed here is to structurally characterize the inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs). IP3Rs are tetrameric intracellular Ca2+ channels that are predominantly located within the membrane of the endoplasmic reticulum (ER). Ca2+ released by IP3Rs upon stimulation regulates numerous processes including learning and memory, membrane trafficking, synaptic transmission, secretion, motility, membrane excitability, gene expression, cell division and apoptosis. Deregulation of IP3Rs results in pathological changes in Ca2+ signaling leading to apoptosis or abnormal growth, and is implicated in the pathogenesis of several neurodegenerative diseases and cancer. More specifically, among the 3 subtypes of IP3Rs, the type 3 IP3R (IP3R-3) is emerging as a viable therapeutic target against diverse diseases including cancer. Despite recent advances in structural characterization of IP3Rs, understanding of the molecular mechanisms regulating IP3R activity remains incomplete. Our preliminary cryo-EM studies revealed an unanticipated regulatory mechanism where a loop extending from the regulatory ARM2 domain interacts with the IP3 binding domain. Here, using the facilities in Pacific Northwest Cryo-EM Center, we aim to;1) solve the structure of IP3R-3s in the resting state at a higher resolution that would facilitate modeling of the regulatory loop we discovered.
2) solve the structure of IP3R-3s in the active state to deduce the molecular mechanism of channel gating.
Completion of this aim will open new avenues towards the molecular characterization of IP3R activity and regulation, providing novel structural information about the mechanism and architecture of the IP3R-3.
Project Details
Start Date
2019-11-10
End Date
2020-08-10
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members