Identification of Functionally Critical Residues in the Channel Domain of Inositol Trisphosphate Receptors

Bhanumathy, Cunnigaiper D.; Fonseca, Paula C. A. da; Morris, Edward P.; Joseph, Suresh K.

doi:10.1074/jbc.m112.415786

Cited by 26 publications

(28 citation statements)

References 55 publications

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“…These studies provide a structural basis to explain our data whereby the expressed fragmented receptor can associate through non-covalent interactions in vivo. Mutagenesis of key residues in the suppressor domain and the transmembrane linker also indicates that these interactions are pivotally important for transducing the conformational change induced by IP 3 binding to opening of the pore (5,(52)(53)(54). These data indicate that a conformational change transmitted through the entire linear peptide sequence of the cytosolic domain of the protein is not necessary for gating.…”

Section: Discussionmentioning

confidence: 59%

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Alzayady

Chandrasekhar

Yule

2013

Journal of Biological Chemistry

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Background: Proteolytic cleavage and disruption of inositol 1,4,5-trisphosphate receptor (IP 3 R) architecture may contribute to the initiation/progression of apoptosis. Results: Proteolytic cleavage products of the IP 3 R remain membrane-associated, and these fragments form functional tetrameric channels. Conclusion: Fragmentation of the IP 3 R does not inevitably lead to loss of function. Significance: Peptide continuity is not required for IP 3 R function, and IP 3 R activation may persist after protease cleavage during apoptosis.

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Section: Discussionmentioning

confidence: 59%

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Alzayady

Chandrasekhar

Yule

2013

Journal of Biological Chemistry

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“…While modulation of the InsP 3 R channel function has not been investigated regarding its sensitivity to Zn 2+ , this domain may have a role in coordinating metals that influence channel gating. Mutational studies of the C2H2 residues were shown to either inhibit (Cys2611Ser, Cys2614Ser, His2636Ala) or completely abolish (His2631Ala) channel function, indicating that the LNK domain is positioned to be a crucial structural component for allosteric modulation of channel gating 21,32 .…”

Section: Gating Via C- and N-terminal Couplingmentioning

confidence: 99%

Gating machinery of InsP3R channels revealed by electron cryomicroscopy

Fan

Baker

Wang

et al. 2015

Nature

206

302

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Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca2+ signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure–function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 Å) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously ~85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca2+-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed α-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.

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“…Similar to residues in the LBD and selectivity filter, residue I2550 is also associated with multiple diseases as mutation I2550N is causative for pontocerebellar hypoplasia (PCH), while mutation I2550T is causative for SCA29 (Zambonin et al, 2017, van Dijk et al, 2017). The I2550 residue has been previously identified as potentially structurally significant as it may serve as a constriction site in the channel pore (Baker et al, 2017, Fan et al, 2015, Bhanumathy et al, 2012). Substitution of the highly conserved, hydrophobic Ile, by either Thr or Asn, would likely disrupt the TM domain and affect Ca 2+ signaling.…”

Section: Ip3r Mutations Associated With Human Disease By Domain: Mutamentioning

confidence: 99%

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

et al. 2018

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Summary Calcium release into the cytosol via the inositol 1,4,5-trisphosphate receptor (IP3R) calcium channel is important for a variety of cellular processes. As a result, impairment or inhibition of this release can result in disease. Recently, mutations in all four domains of the IP3R have been suggested to cause diseases such as ataxia, cancer, and anhidrosis; however, most of these mutations have not been functionally characterized. In this review we summarize the reported mutations, as well as the associated symptoms. Additionally, we use clues from transgenic animals, receptor stoichiometry, and domain location of mutations to speculate on the effects of individual mutations on receptor structure and function and the overall mechanism of disease.

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Identification of Functionally Critical Residues in the Channel Domain of Inositol Trisphosphate Receptors

Cited by 26 publications

References 55 publications

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Gating machinery of InsP3R channels revealed by electron cryomicroscopy

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

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