Structure of IP3R channel: high-resolution insights from cryo-EM

• Published in: Current opinion in structural biology 2017-10, Vol.46, p.38-47
• Main Authors: Baker, Mariah R, Fan, Guizhen, Serysheva, Irina I
• Format: Article
• Language: English
• ISSN: 0959-440X; 1879-033X; 1879-033X
• DOI: 10.1016/j.sbi.2017.05.014

•Full-length tetrameric structure of IP3R1 has been solved at 4.7Å resolution.•The overall structure was validated by multiple methods.•The central four-helix bundle provides a supporting scaffold for the cytosolic assembly.•Direct structural coupling between the C-terminal and IP3-binding domains is revealed.•Versatility of Ca2+ signaling via IP3R is founded in the architecture of cytosolic domains. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ubiquitously expressed intracellular Ca2+ channels and the major mediators of cellular Ca2+ signals generated by the release of Ca2+ ions from intracellular stores in response to a variety of extracellular stimuli. Despite established physiological significance and proven involvements of IP3R channels in many human diseases, detailed structural basis for signal detection by these ion channels and their gating remain obscure. Recently, single particle electron cryomicroscopy (cryo-EM) has yielded a long-awaited near-atomic resolution structure of the entire full-length type 1 IP3R. This structure provided exciting mechanistic insights into the molecular assembly of IP3R, revealing the pronounced structural conservation of Ca2+ release channels and raising many fundamental and controversial questions on their activation and gating. Here we summarize the major technological advances that propelled our cryo-EM analysis of IP3R to near-atomic resolution and discuss what the future holds for structural biology of Ca2+ release channels.