scholarly journals Two-state Conformational Changes in Inositol 1,4,5-Trisphosphate Receptor Regulated by Calcium

2002 ◽  
Vol 277 (24) ◽  
pp. 21115-21118 ◽  
Author(s):  
Kozo Hamada ◽  
Tomoko Miyata ◽  
Kouta Mayanagi ◽  
Junji Hirota ◽  
Katsuhiko Mikoshiba
Keyword(s):  
Conformational Changes ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Ligand-induced Conformational Changes via Flexible Linkers in the Amino-terminal region of the Inositol 1,4,5-Trisphosphate Receptor

2007 ◽  
Vol 373 (5) ◽  
pp. 1269-1280 ◽  
Author(s):  
Jenny Chan ◽  
Andrew E. Whitten ◽  
Cy M. Jeffries ◽  
Ivan Bosanac ◽  
Tapas K. Mal ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Terminal Region ◽  
Amino Terminal ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

A new mechanism in the binding between Homer3 EVH1 domain and inositol 1,4,5 trisphosphate receptor suppressor domain

2014 ◽  
Vol 92 (3) ◽  
pp. 163-171
Author(s):  
He Wen ◽  
Hyuk Nam Kwon ◽  
Sunghyouk Park
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Large Scale ◽  
Critical Role ◽  
Binding Assays ◽  
Binding Characteristics ◽  
Binding Partners ◽  
Inositol 1,4,5 Trisphosphate ◽  
Target Binding ◽  
Trisphosphate Receptor

The suppressor domain of inositol 1,4,5 trisphosphate receptor (IP3R) has critical roles in regulating the calcium channel by interacting with many binding partners. The residue 49–53 (PPKKF) of the suppressor domain was suggested to be a canonical Homer EVH1 domain binding site and is also the first a part of calmodulin (CaM) binding site. As CaM-binding of the suppressor domain has been shown to involve large-scale conformational changes, we studied the binding characteristics of the Homer EVH1-suppressor domain with NMR spectroscopy and biochemical pull-down assays for mutants. Our data show that the suppressor domain employs the PPKKF motif in a similar but subtly different way compared to previously characterized interactions, and that the suppressor domain does not undergo large-scale conformational changes. Chemical shift assignments of the Homer3 EVH1 domain found that a new set of residues, located at the opposite side of the previously reported binding site, is also involved in binding, which was confirmed by mutant binding assays. Further analysis suggests that F40 in the new binding sites may have a critical role as a conformational lock-switch in Homer-target binding. The proposed mechanism is implicated in the signaling network involving calcium channels.

scholarly journals Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent intramolecular interaction

2004 ◽  
Vol 381 (1) ◽  
pp. 87-96 ◽  
Author(s):  
Geert BULTYNCK ◽  
Karolina SZLUFCIK ◽  
Nael Nadif KASRI ◽  
Zerihun ASSEFA ◽  
Geert CALLEWAERT ◽  
...  
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Intramolecular Interaction ◽  
Binding Activity ◽  
Release Channel ◽  
B Lymphoma Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Adenophostin A ◽  
Binding Core ◽  
Trisphosphate Receptor

Thiol-reactive agents such as thimerosal have been shown to modulate the Ca2+-flux properties of IP3 (inositol 1,4,5-trisphosphate) receptor (IP3R) via an as yet unidentified mechanism [Parys, Missiaen, De Smedt, Droogmans and Casteels (1993) Pflügers Arch. 424, 516–522; Kaplin, Ferris, Voglmaier and Snyder (1994) J. Biol. Chem. 269, 28972–28978; Missiaen, Taylor and Berridge (1992) J. Physiol. (Cambridge, U.K.) 455, 623–640; Missiaen, Parys, Sienaert, Maes, Kunzelmann, Takahashi, Tanzawa and De Smedt (1998) J. Biol. Chem. 273, 8983–8986]. In the present study, we show that thimerosal potentiated IICR (IP3-induced Ca2+ release) and IP3-binding activity of IP3R1, expressed in triple IP3R-knockout R23-11 cells derived from DT40 chicken B lymphoma cells, but not of IP3R3 or [Δ1–225]-IP3R1, which lacks the N-terminal suppressor domain. Using a 45Ca2+-flux technique in permeabilized A7r5 smooth-muscle cells, we have shown that Ca2+ shifted the stimulatory effect of thimerosal on IICR to lower concentrations of thimerosal and thereby increased the extent of Ca2+ release. This suggests that Ca2+ and thimerosal synergetically regulate IP3R1. Glutathione S-transferase pull-down experiments elucidated an interaction between amino acids 1–225 (suppressor domain) and amino acids 226–604 (IP3-binding core) of IP3R1, and this interaction was strengthened by both Ca2+ and thimerosal. In contrast, calmodulin and sCaBP-1 (short Ca2+-binding protein-1), both having binding sites in the 1–225 region, weakened the interaction. This interaction was not found for IP3R3, in agreement with the lack of functional stimulation of this isoform by thimerosal. The interaction between the IP3-binding and transmembrane domains (amino acids 1–604 and 2170–2749 respectively) was not affected by thimerosal and Ca2+, but it was significantly inhibited by IP3 and adenophostin A. Our results demonstrate that thimerosal and Ca2+ induce isoform-specific conformational changes in the N-terminal part of IP3R1, leading to the formation of a highly IP3-sensitive Ca2+-release channel.

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