5x9z
Crystal structure of inositol 1,4,5-trisphosphate receptor large cytosolic domain
Structural highlights
FunctionITPR1_MOUSE Intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate. Plays a role in ER stress-induced apoptosis. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CaM kinase II, eventually leading to the activation of downstream apoptosis pathways.[1] [2] [3] Publication Abstract from PubMedThe inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is an IP3-gated ion channel that releases calcium ions (Ca2+) from the endoplasmic reticulum. The IP3-binding sites in the large cytosolic domain are distant from the Ca2+ conducting pore, and the allosteric mechanism of how IP3 opens the Ca2+ channel remains elusive. Here, we identify a long-range gating mechanism uncovered by channel mutagenesis and X-ray crystallography of the large cytosolic domain of mouse type 1 IP3R in the absence and presence of IP3 Analyses of two distinct space group crystals uncovered an IP3-dependent global translocation of the curvature alpha-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP3R channel revealed an essential role of a leaflet structure in the alpha-helical domain. These results suggest that the curvature alpha-helical domain relays IP3-controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP3 binding to the Ca2+ channel. IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography.,Hamada K, Miyatake H, Terauchi A, Mikoshiba K Proc Natl Acad Sci U S A. 2017 May 2;114(18):4661-4666. doi:, 10.1073/pnas.1701420114. Epub 2017 Apr 17. PMID:28416699[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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