Transmembrane topology and sites of N-glycosylation of inositol 1,4,5-trisphosphate receptor.

Michikawa, Takayuki; Hamanaka, Hiroki; Otsu, Hiroko; Yamamoto, Akira; Miyawaki, Atsushi; Furuichi, Teiichi; Tashiro, Yutaka; Mikoshiba, Katsuhiko

doi:10.1016/s0021-9258(17)37092-8

Cited by 129 publications

(11 citation statements)

References 42 publications

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“…To further eliminate background effects, we calculated the relative increments of SOCE or I CRAC when comparing Orai1N223A versus Orai1WT. Our Ca 2+ imaging data do not rule out a role for glycosylation of other store-related proteins, such as the ER-localized Ca 2+ -ATPase SERCA or IP 3 receptors (71,72).…”

Section: Discussioncontrasting

confidence: 76%

Cell type–specific glycosylation of Orai1 modulates store-operated Ca ²⁺ entry

et al. 2016

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N-glycosylation of cell surface proteins affects protein function, stability, and interaction with other proteins. Orai channels, which mediate store-operated Ca(2+) entry (SOCE), are composed of N-glycosylated subunits. Upon activation by Ca(2+) sensor proteins (stromal interaction molecules STIM1 or STIM2) in the endoplasmic reticulum, Orai Ca(2+) channels in the plasma membrane mediate Ca(2+) influx. Lectins are carbohydrate-binding proteins, and Siglecs are a family of sialic acid-binding lectins with immunoglobulin-like repeats. Using Western blot analysis and lectin-binding assays from various primary human cells and cancer cell lines, we found that glycosylation of Orai1 is cell type-specific. Ca(2+) imaging experiments and patch-clamp experiments revealed that mutation of the only glycosylation site of Orai1 (Orai1N223A) enhanced SOCE in Jurkat T cells. Knockdown of the sialyltransferase ST6GAL1 reduced α-2,6-linked sialic acids in the glycan structure of Orai1 and was associated with increased Ca(2+) entry in Jurkat T cells. In human mast cells, inhibition of sialyl sulfation altered the N-glycan of Orai1 (and other proteins) and increased SOCE. These data suggest that cell type-specific glycosylation influences the interaction of Orai1 with specific lectins, such as Siglecs, which then attenuates SOCE. In summary, the glycosylation state of Orai1 influences SOCE-mediated Ca(2+) signaling and, thus, may contribute to pathophysiological Ca(2+) signaling observed in immune disease and cancer.

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Section: Discussioncontrasting

confidence: 76%

Cell type–specific glycosylation of Orai1 modulates store-operated Ca ²⁺ entry

et al. 2016

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“…A six-TMR model is consistent with immunogold electron microscopy studies showing that the NH 2 and COOH termini are both localized in the cytoplasm (Mignery et al, 1989). It is also consistent with glycosylation data that demonstrates that the loop between the fifth and sixth TMR is lumenal (Michikawa et al, 1994). Moreover, the six-TMR model was experimentally confirmed by differential permeabilization combined with immunohistochemistry (Galvan, D., E. Borrego-Diaz, P.J.…”

Section: Introductionsupporting

confidence: 83%

Location of the Permeation Pathway in the Recombinant Type 1 Inositol 1,4,5-Trisphosphate Receptor

Ramos-Franco

Galvan

Mignery

et al. 1999

The Journal of General Physiology

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The inositol 1,4,5-trisphosphate receptor (InsP3R) forms ligand-regulated intracellular Ca2+ release channels in the endoplasmic reticulum of all mammalian cells. The InsP3R has been suggested to have six transmembrane regions (TMRs) near its carboxyl terminus. A TMR-deletion mutation strategy was applied to define the location of the InsP3R pore. Mutant InsP3Rs were expressed in COS-1 cells and single channel function was defined in planar lipid bilayers. Mutants having the fifth and sixth TMR (and the interceding lumenal loop), but missing all other TMRs, formed channels with permeation properties similar to wild-type channels (gCs = 284; gCa = 60 pS; P Ca/P Cs = 6.3). These mutant channels bound InsP3, but ligand occupancy did not regulate the constitutively open pore (P o > 0.80). We propose that a region of 191 amino acids (including the fifth and sixth TMR, residues 2398–2589) near the COOH terminus of the protein forms the InsP3R pore. Further, we have produced a constitutively open InsP3R pore mutant that is ideal for future site-directed mutagenesis studies of the structure–function relationships that define Ca2+ permeation through the InsP3R channel.

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“…Furthermore, down-regulation of calreticulin expression with an antisense oligodeoxynucleotide results in the inhibition of bradykininmediated InsP $ -dependent Ca# + release from the ER in neuroblastomaiglioma NG-108-15 cells [205]. An attractive hypothesis is that, similar to SERCA-calreticulin interactions, calreticulin may bind to the glycosylated intraluminal loop(s) of the InsP $ receptor and modulate Ca# + release [206]. The protein may also play an important role in chaperoning of both InsP $ receptor and\or molecules involved in the InsP $ pathway.…”

Section: Calreticulin and Insp 3 -Dependent Ca 2 + Releasementioning

confidence: 99%

Calreticulin: one protein, one gene, many functions

Michalak¹,

Corbett²,

Mesaeli³

et al. 1999

Biochem. J.

491

345

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The endoplasmic reticulum (ER) plays a critical role in the synthesis and chaperoning of membrane-associated and secreted proteins. The membrane is also an important site of Ca(2+) storage and release. Calreticulin is a unique ER luminal resident protein. The protein affects many cellular functions, both in the ER lumen and outside of the ER environment. In the ER lumen, calreticulin performs two major functions: chaperoning and regulation of Ca(2+) homoeostasis. Calreticulin is a highly versatile lectin-like chaperone, and it participates during the synthesis of a variety of molecules, including ion channels, surface receptors, integrins and transporters. The protein also affects intracellular Ca(2+) homoeostasis by modulation of ER Ca(2+) storage and transport. Studies on the cell biology of calreticulin revealed that the ER membrane is a very dynamic intracellular compartment affecting many aspects of cell physiology.

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Transmembrane topology and sites of N-glycosylation of inositol 1,4,5-trisphosphate receptor.

Cited by 129 publications

References 42 publications

Cell type–specific glycosylation of Orai1 modulates store-operated Ca ²⁺ entry

Cell type–specific glycosylation of Orai1 modulates store-operated Ca ²⁺ entry

Location of the Permeation Pathway in the Recombinant Type 1 Inositol 1,4,5-Trisphosphate Receptor

Calreticulin: one protein, one gene, many functions

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Transmembrane topology and sites of N-glycosylation of inositol 1,4,5-trisphosphate receptor.

Cited by 129 publications

References 42 publications

Cell type–specific glycosylation of Orai1 modulates store-operated Ca 2+ entry

Cell type–specific glycosylation of Orai1 modulates store-operated Ca 2+ entry

Location of the Permeation Pathway in the Recombinant Type 1 Inositol 1,4,5-Trisphosphate Receptor

Calreticulin: one protein, one gene, many functions

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Product

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Cell type–specific glycosylation of Orai1 modulates store-operated Ca ²⁺ entry

Cell type–specific glycosylation of Orai1 modulates store-operated Ca ²⁺ entry