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

Hamada, Kozo; Miyata, Tomoko; Mayanagi, Kouta; Hirota, Junji; Mikoshiba, Katsuhiko

doi:10.1074/jbc.c200244200

Cited by 84 publications

(83 citation statements)

References 26 publications

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“…In each case, labeling studies with gold-heparin appeared to locate the IP 3 -binding site to the peripheral domains (i.e., the tips of the sails of the windmill). Our 3D structure (determined in the absence of Ca 2ϩ ), which measures about 18 ϫ 18 ϫ 18 nm and is approximately square in both top and side projections, corresponds more closely with the square structure observed by Hamada et al (31). However, the peripheral location of the IP 3 -binding domain suggested by heparin-gold labeling (31) is not consistent with recent studies (32) suggesting that the IP 3 -binding sites within a tetrameric receptor are no more than 2 nm apart.…”

Section: Comparison With Previous Structural Data On the Ip3rsupporting

confidence: 52%

“…However, the peripheral location of the IP 3 -binding domain suggested by heparin-gold labeling (31) is not consistent with recent studies (32) suggesting that the IP 3 -binding sites within a tetrameric receptor are no more than 2 nm apart. It is possible that the large size of the heparin, gold, and linker may have exaggerated the separation of the IP 3 -binding sites in the labeling study (31).…”

Section: Comparison With Previous Structural Data On the Ip3rmentioning

confidence: 99%

“…Particles of 12-nm width observed in these freeze-etch studies may well represent channel domains. More recently, IP 3 R has been studied by negative-staining electron microscopy as a function of Ca 2ϩ concentration (31). A ''windmill''-shaped structure measuring 31 nm diagonally predominated at elevated Ca 2ϩ concentration, whereas a more compact square structure with sides measuring 19 nm predominated in the absence of Ca 2ϩ .…”

Section: Comparison With Previous Structural Data On the Ip3rmentioning

confidence: 99%

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Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis

Fonseca¹,

Morris²,

Nerou³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Materials and Methods Purification of IP3R.A membrane fraction was prepared from rat cerebella (17), resuspended (50 mg͞ml in 50 mM Tris͞1 mM EDTA, pH 8.3), and solubilized by the addition of 1% Triton X-100. After centrifugation (100,000 ϫ g for 60 min), the supernatant, supplemented with 250 mM NaCl, was loaded onto an Econopac heparin column (1 ml, Bio-Rad), washed with 25 ml of medium A (50 mM Tris͞250 mM NaCl͞10% glycerol, pH 8.3), supplemented with 1 mM EDTA, 1% Surfact-Amps X-100 (Pierce), and then with medium A supplemented with 0.1% Surfact-Amps X-100 (50 ml). IP 3 R was eluted from the heparin column directly onto a 2-ml Con A-agarose column (Sigma) by using medium A supplemented with 0.1% Surfact-Amps X-100 and 50 M decavanadate (18). After washing with 150 ml of medium B (50 mM Tris͞100 mM NaCl͞10% glycerol͞0.1% Surfact-Amps X-100, pH 8.3), IP 3 R was eluted by overnight incubation with 4 ml of medium B containing 800 mM methyl mannopyranoside (17). To assess the quaternary structure of the purified receptor, 0.2-ml fractions of the final eluate were loaded onto linear 10-30% sucrose gradients (10 ml) in 50 mM Tris͞1 mM EDTA͞0.1% Surfact-Amps X-100, pH 8.3, and centrifuged (134,000 ϫ g for 60 min). Gradients were calibrated by using a high-molecular-weight gel filtration standards kit (Amersham Biosciences). Size-exclusion HPLC was preformed by using a Zorbax GF-450 column (Jones Chromatography, Lakewood, CO) coupled to a Kontron system (Kontron Instruments, Watford, U.K.). All media included the following mixture of protease inhibitors: 150 nM aprotinin, 1 M pepstatin, 20 g͞ml soybean trypsin inhibitor, 1 mM benzamidine, 250 M PMSF, 250 M captopril, and 1 M bestatin.

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Section: Comparison With Previous Structural Data On the Ip3rsupporting

confidence: 52%

Section: Comparison With Previous Structural Data On the Ip3rmentioning

confidence: 99%

Section: Comparison With Previous Structural Data On the Ip3rmentioning

confidence: 99%

See 1 more Smart Citation

Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis

Fonseca¹,

Morris²,

Nerou³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Functional IP 3 Rs are tetrameric, assembled either from identical subunits or from mixtures of the three subtypes and their many splice variants Foskett et al 2007). Several structures of the entire IP 3 R1 have been published, each derived from single particle analysis of images from electron microscopy (Hamada and Mikoshiba 2002;Jiang et al 2002a;da Fonseca et al 2003;Hamada et al 2003;Serysheva et al 2003;Sato et al 2004). These studies confirm the tetrameric state of IP 3 R, but variability between the structures and their relatively low resolution ( 30 Å ) have, so far, limited any realistic interpretation of the structural basis of IP 3 R activation (Fig.…”

Section: Structural Determinants Of Ip 3 R Activationmentioning

confidence: 99%

IP3 Receptors: Toward Understanding Their Activation

Taylor¹,

Tovey²

2010

Cold Spring Harbor Perspectives in Biology

252

185

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Inositol 1,4,5-trisphosphate receptors (IP 3 R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca 2þ release from intracellular stores. Their regulation by Ca 2þ allows them also to propagate cytosolic Ca 2þ signals regeneratively. This brief review addresses the structural basis of IP 3 R activation by IP 3 and Ca 2þ . IP 3 initiates IP 3 R activation by promoting Ca 2þ binding to a stimulatory Ca 2þ -binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP 3 with opposite sides of the clam-like IP 3 -binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP 3 R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP 3 R.

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“…From our early EM studies of negatively stained IP 3 R1 using heparin-gold labeling, we proposed a long-range coupling of IBD to the channel domain by Ca 2+ -dependent structural changes (84)(85)(86). However, direct binding of the IBD to the channel domain was postulated, and a model was proposed in which an N-terminal suppressor domain directly binds a loop between putative transmembrane helices (87)(88)(89)(90).…”

Section: Discussionmentioning

confidence: 99%

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

Hamada

Terauchi

Nakamura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The inositol 1,4,5-trisphosphate receptor (IP 3 R) in the endoplasmic reticulum mediates calcium signaling that impinges on intracellular processes. IP 3 Rs are allosteric proteins comprising four subunits that form an ion channel activated by binding of IP 3 at a distance. Defective allostery in IP 3 R is considered crucial to cellular dysfunction, but the specific mechanism remains unknown. Here we demonstrate that a pleiotropic enzyme transglutaminase type 2 targets the allosteric coupling domain of IP 3 R type 1 (IP 3 R1) and negatively regulates IP 3 R1-mediated calcium signaling and autophagy by locking the subunit configurations. The control point of this regulation is the covalent posttranslational modification of the Gln2746 residue that transglutaminase type 2 tethers to the adjacent subunit. Modification of Gln2746 and IP 3 R1 function was observed in Huntington disease models, suggesting a pathological role of this modification in the neurodegenerative disease. Our study reveals that cellular signaling is regulated by a new mode of posttranslational modification that chronically and enzymatically blocks allosteric changes in the ligand-gated channels that relate to disease states.L igand-gated ion channels function by allostery that is the regulation at a distance; the allosteric coupling of ligand binding with channel gating requires reversible changes in subunit configurations and conformations (1). Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are ligand-gated ion channels that release calcium ions (Ca 2+ ) from the endoplasmic reticulum (ER) (2, 3). IP 3 Rs are allosteric proteins comprising four subunits that assemble a calcium channel with fourfold symmetry about an axis perpendicular to the ER membrane. The subunits of three IP 3 R isoforms (IP 3 R1, IP 3 R2, and IP 3 R3) are structurally divided into three domains: the IP 3 -binding domain (IBD), the regulatory domain, and the channel domain (3-6). Fitting of the IBD X-ray structures (7, 8) to a cryo-EM map (9) indicates that the IBD activates a remote Ca 2+ channel by allostery (8); however, the current X-ray structure only spans 5% of each tetramer, such that the mechanism underlying allosteric coupling of the IBD to channel gating remains unknown.The IP 3 R in the ER mediates intracellular calcium signaling that impinges on homeostatic control in various subsequent intracellular processes. Deletion of the genes encoding the type 1 IP 3 R (IP 3 R1) leads to perturbations in long-term potentiation/ depression (3, 10, 11) and spinogenesis (12), and the human genetic disease spinocerebellar ataxia 15 is caused by haploinsufficiency of the IP 3 R1 gene (13-15). Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16-18) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23, 24), autophagy regulation (24-27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophag...

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

Cited by 84 publications

References 26 publications

Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis

Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis

IP3 Receptors: Toward Understanding Their Activation

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

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