title: The role of the S4-S5 linker and C-terminal tail in inositol 1,4,5-trisphosphate receptor function.
abstract: In previous studies we have suggested that spatial proximity of the C- and N-terminal domains of inositol 1,4,5-trisphosphate receptors (IP(3)Rs) may be critical for the channel gating mechanism. In the present study we have examined the sites of C-N interaction in more detail. We report that deletion mutations within the S4-S5 linker (amino acids 2418-2437) prevent co-immunoprecipitation of the C- and N-terminal domains, inhibit channel activity and enhance IP(3) binding. We also show that a region of the C-terminal tail (amino acids 2694-2721), predicted to be a coiled-coil, is also required for channel activity. Circular dichroism spectroscopy and gel filtration studies confirm that this region has a helical structure with the ability to form tetramers. We propose a model in which IP(3)-induced conformational changes in the N-terminal domain are mechanically transmitted to the opening of the pore through an attachment to the S4-S5 linker. The coiled-coil domain in the C-terminal tail may play a critical role in maintaining the structural integrity of the channel.
authors.affiliation: Department of Pathology, Cell Biology, and Anatomy, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Schug
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Joseph
mesh_terms: D000818:Animals; D019556:COS Cells; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism; D002522:Chlorocebus aethiops; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015640:Ion Channel Gating; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins