Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

Bosanac, Ivan; Alattia, Jean René; Mal, Tapas K.; Chan, Jimmy Yu‐Wai; Talarico, Susanna; Tong, Frances; Tong, Kit I.; Yoshikawa, Fumio; Furuichi, Teiichi; Iwai, Miwako; Michikawa, Takayuki; Mikoshiba, Katsuhiko; Ikura, Mitsuhiko

doi:10.1038/nature01268

Cited by 305 publications

(394 citation statements)

References 28 publications

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“…Because of the absence of a high-resolution structure for any domain in RyR1, we used comparative modeling to further interpret the structure. Using sequence and structural analysis (16)(17)(18), a structural homolog was identified with high confidence for two segments at the RyR1 N terminus: the ligand-binding suppressor domain [Protein Data Bank (PDB) ID code 1XZZ (19)] for residues Q12-S207 and the IP 3 -binding core region [PDB ID code 1N4K (20)] of the type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1) for residues G216-Y565 (Fig. 3A and Figs.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel

Serysheva¹,

Ludtke²,

Baker³

et al. 2008

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

104

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The skeletal muscle Ca 2؉ release channel (RyR1), a homotetramer, regulates the release of Ca 2؉ from the sarcoplasmic reticulum to initiate muscle contraction. In this work, we have delineated the RyR1 monomer boundaries in a subnanometer-resolution electron cryomicroscopy (cryo-EM) density map. In the cytoplasmic region of each RyR1 monomer, 36 ␣-helices and 7 ␤-sheets can be resolved. A ␤-sheet was also identified close to the membranespanning region that resembles the cytoplasmic pore structures of inward rectifier K ؉ channels. Three structural folds, generated for amino acids 12-565 using comparative modeling and cryo-EM density fitting, localize close to regions implicated in communication with the voltage sensor in the transverse tubules. Eleven of the 15 disease-related residues for these domains are mapped to the surface of these models. Four disease-related residues are found in a basin at the interfaces of these regions, creating a pocket in which the immunophilin FKBP12 can fit. Taken together, these results provide a structural context for both channel gating and the consequences of certain malignant hyperthermia and central core disease-associated mutations in RyR1.Ca 2ϩ release channels ͉ cryo-EM ͉ 3D Structure ͉ modeling

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Section: Resultsmentioning

confidence: 99%

“…Residues G216 -Y565 share a fold with the IP 3-binding core of the IP3R1 channel (PDB ID code 1N4K, sequence identity 16%) (Figs. S2 and S3) (20).…”

Section: Methodsmentioning

confidence: 99%

Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel

Serysheva¹,

Ludtke²,

Baker³

et al. 2008

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

104

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“…Stimulation of IP 3 R by cytosolic Ca 2þ is universally observed even with purified IP 3 R reconstituted into lipid bilayers (Ferris et al 1989;Hirota et al 1995;Michikawa et al 1999), suggesting that this essential Ca 2þ -binding site probably resides within the primary sequence of the IP 3 R. At least seven cytosolic Ca 2þ -binding sites have been identified within IP 3 R1 (Sienaert et al 1996;Sienaert et al 1997), but the physiological relevance of these sites is unresolved. Two of the sites (residues 304-381 and 378-450) are within the IP 3 -binding core, for which there is a high-resolution structure (Bosanac et al 2002). This structure shows two surface-exposed clusters of acidic residues that overlap with residues in the second N-terminal Ca 2þ -binding region.…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 99%

“…It is noteworthy that neither of the immediate products of IP 3 metabolism, IP 2 and IP 4 , binds to the IBC; both metabolic pathways are therefore effective means of terminating activation of IP 3 R by IP 3 . An atomic structure of the IBC with IP 3 bound (Bosanac et al 2002) shows IP 3 held within a clam-like structure in which the phosphate groups of IP 3 are coordinated by basic residues (Fig. 3A).…”

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

263

190

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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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“…The recent solving of the crystal structure of the type I IP 3 R LBD has revealed that it consists of an N-terminal ␤-domain forming a ␤-trefoil fold, hinged to an all-helical C-terminal domain containing three armadillo-repeat-like structures (26) (Fig. 5A).…”

Section: The All-helical Fragment Of the Ip3r Lbd Is Sufficient To Opmentioning

confidence: 99%

Targeted expression of the inositol 1,4,5-triphosphate receptor (IP ₃ R) ligand-binding domain releases Ca ²⁺ via endogenous IP ₃ R channels

Várnai

Balla

Hunyady

et al. 2005

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

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Ca 2ϩ channel ͉ endoplasmic reticulum ͉ red fluorescent protein T he intracellular second messenger, inositol 1,4,5-trisphosphate (IP 3 ) is generated upon stimulation of cell-surface receptors linked to phospholipase C (PLC) activation (1). IP 3 rapidly binds to an intracellular receptor and releases Ca 2ϩ from intracellular Ca 2ϩ stores; hence, both IP 3 and its receptor (IP 3 R) are key components of the signal transduction mechanism that links cell-surface receptors to calcium-regulated intracellular responses (2). All three isoforms of the IP 3 R (types I, II, and III) function as intracellular Ca 2ϩ channels that work as homotetramers or heterotetramers (3). Each receptor subunit has a channel portion containing six transmembrane helices and a pore domain located between TM5 and TM6, close to the C terminus of the protein (4-6). The ligand-binding domain (LBD) of the receptor is located at the N terminus (7) and is separated from the channel domain by a long intervening regulatory region facing the cytoplasm (3, 7). IP 3 binding leads to rapid activation of the channel, but Ca 2ϩ -induced Ca 2ϩ release, similar to that characteristic of the related ryanodine receptors (RyRs), has also been recognized as an important regulatory feature of IP 3 Rs (8). Because of this complex, and often subtype-specific, regulation of IP 3 channels, cells can display complex Ca 2ϩ wave patterns and oscillations after agonist stimulation, the shape and frequency of which can have unique importance in the selective regulation of downstream effectors (9-11).Despite intense studies, little is known about the manner in which the binding of IP 3 to the N-terminal LBD affects the channel gating properties of the molecule. Upon IP 3 binding, the LBD undergoes a significant conformational change as evidenced by the IP 3 -induced alteration of its migration on a size-exclusion column (7) and by its suitability as a FRET-based sensor of IP 3 binding (12). As shown recently, the C-terminal channel domain, isolated from the rest of the receptor, is constitutively active, and the presence of the regulatory domain is required to maintain the suppression of channel activity (13,14). Moreover, elegant cross-linking experiments have shown that the N-terminal domain of the receptor is in juxtaposition with the C-terminal channel domain (15). These data together raised the possibility that the proximity of the LBD to the channel domain may be an important aspect of IP 3 R regulation after binding of IP 3 . The present study was designed to investigate whether the LBD of the IP 3 R acts as a tethered regulatory module that regulates the channel activity via IP 3 -induced conformational changes. For this purpose, we used a molecular approach by which the isolated LBD of type I IP 3 R or its components was tethered to the cytoplasmic surface of the endoplasmic reticulum (ER), and the effects of their expression on Ca 2ϩ signaling was compared with those of the same constructs expressed in the cytoplasm. These experiments revealed that the all-heli...

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Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

Cited by 305 publications

References 28 publications

Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel

Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel

IP3 Receptors: Toward Understanding Their Activation

Targeted expression of the inositol 1,4,5-triphosphate receptor (IP ₃ R) ligand-binding domain releases Ca ²⁺ via endogenous IP ₃ R channels

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Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

Cited by 305 publications

References 28 publications

Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel

Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel

IP3 Receptors: Toward Understanding Their Activation

Targeted expression of the inositol 1,4,5-triphosphate receptor (IP 3 R) ligand-binding domain releases Ca 2+ via endogenous IP 3 R channels

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Targeted expression of the inositol 1,4,5-triphosphate receptor (IP ₃ R) ligand-binding domain releases Ca ²⁺ via endogenous IP ₃ R channels