A molecular specificity code for the three mammalian KDEL receptors

Raykhel, Irina; Alanen, Heli I.; Salo, Kirsi E.H.; Jurvansuu, Jaana; Nguyen, Van Dat; Latva-Ranta, Maria; Ruddock, Lloyd W.

doi:10.1083/jcb.200705180

Cited by 218 publications

(229 citation statements)

References 29 publications

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“…AGR2 was initially assumed to be a secreted protein, based on the presence of a predicted signal peptide at the amino terminus (8). However, more recent analysis identified an ER localization signal and thioredoxin-like domain sequences, suggesting that AGR2 is a PDI (3,12). We found that AGR2 is localized to the ER in intestinal epithelial cells and did not detect AGR2 in secretory granules or in the intestinal lumen.…”

Section: Discussionmentioning

confidence: 60%

“…AGR2 was originally presumed to be another secreted protein produced by goblet cells (8). However, AGR2 has a carboxyl-terminal KTEL sequence, and a recent analysis indicated that this sequence was recognized by ER retention receptors and served to localize AGR2 predominantly to the ER of transfected cells (12). In addition, AGR2 has a single thioredoxin-like domain with a CXXS motif (3).…”

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confidence: 99%

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The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

Park

Zhen²,

Verhaeghe³

et al. 2009

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

340

374

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Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals, but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells. Here, we show that AGR2 is present within the ER of intestinal secretory epithelial cells and is essential for in vivo production of the intestinal mucin MUC2, a large, cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxinlike domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. Mice lacking AGR2 were viable but were highly susceptible to colitis, indicating a critical role for AGR2 in protection from disease. We conclude that AGR2 is a unique member of the PDI family, with a specialized and nonredundant role in intestinal mucus production.colitis ͉ endoplasmic reticulum ͉ mucin ͉ goblet cell ͉ protein processing

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

Park

Zhen²,

Verhaeghe³

et al. 2009

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

340

374

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“…6A, Upper Right). The increased ER targeting efficiency of H8-KDEL is likely through the retrograde transport system from Golgi to ER via the KDEL receptors (30)(31)(32). In vivo, the H8-KDEL peptide caused mislocalization of rhodopsin to the inner segment and perinuclear ER region (yellow and white arrows, respectively, in Fig.…”

Section: Disruption By Helix Peptides Of R-and S-opsin Trafficking Inmentioning

confidence: 99%

Dimerization of visual pigments in vivo

Zhang

Cao

Kumar

et al. 2016

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

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It is a deeply engrained notion that the visual pigment rhodopsin signals light as a monomer, even though many G protein-coupled receptors are now known to exist and function as dimers. Nonetheless, recent studies (albeit all in vitro) have suggested that rhodopsin and its chromophore-free apoprotein, R-opsin, may indeed exist as a homodimer in rod disk membranes. Given the overwhelmingly strong historical context, the crucial remaining question, therefore, is whether pigment dimerization truly exists naturally and what function this dimerization may serve. We addressed this question in vivo with a unique mouse line (S-opsin + Lrat −/− ) expressing, transgenically, short-wavelength-sensitive cone opsin (S-opsin) in rods and also lacking chromophore to exploit the fact that cone opsins, but not R-opsin, require chromophore for proper folding and trafficking to the photoreceptor's outer segment. In R-opsin's absence, S-opsin in these transgenic rods without chromophore was mislocalized; in R-opsin's presence, however, S-opsin trafficked normally to the rod outer segment and produced functional S-pigment upon subsequent chromophore restoration. Introducing a competing R-opsin transmembrane helix H1 or helix H8 peptide, but not helix H4 or helix H5 peptide, into these transgenic rods caused mislocalization of R-opsin and S-opsin to the perinuclear endoplasmic reticulum. Importantly, a similar peptidecompetition effect was observed even in WT rods. Our work provides convincing evidence for visual pigment dimerization in vivo under physiological conditions and for its role in pigment maturation and targeting. Our work raises new questions regarding a potential mechanistic role of dimerization in rhodopsin signaling.rhodopsin | cone opsin | dimerization | protein trafficking R hodopsin and cone pigments mediate scotopic and photopic vision, respectively. They consist of opsin, the apo-protein, and 11-cis-retinal, a vitamin A-based chromophore. Light absorption by 11-cis-retinal triggers a conformational change in opsin, which in turn initiates a G protein-coupled receptor (GPCR) signaling pathway to lead to vision. Indeed, rhodopsin signaling is a prominent prototypical GPCR pathway from which a huge quantity of mechanistic details about such signaling in general has emerged. All along, it is a dogma that rhodopsin exists and functions as a monomer (1-6). About a decade ago, evidence began to emerge that rhodopsin may exist as a dimer, based on atomic force microscopy and cross-linking experiments performed on rod outersegment (ROS) disk membranes (7-9). However, this concept remains highly controversial because of the lack of in vivo evidence and also is puzzling because, unlike many GPCRs, monomeric rhodopsin is fully functional with respect to coupling to G protein (2, 4-6, 10) and to interactions with rhodopsin kinase and arrestin (11,12). In vivo evidence, albeit of paramount importance, is also challenging, because rhodopsin always exists as a single isoform in rod photoreceptors, thus making homomeric, higher-or...

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“…Although a C-terminal KDEL sequence is the canonical retention signal, the KDELRs also have some affinity for similar sequences. An in vitro screen examining the ability of short peptides to interact with the KDELRs revealed 40 -80% percent binding of the RTDL sequence compared with the canonical KDEL sequence (16). It is possible that differences in affinity for the KDELR are important for MANF secretion, and a competition model for ER retention could explain the rapid secretion of MANF in response to ER stress.…”

mentioning

confidence: 99%

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

Henderson

Richie

Airavaara

et al. 2013

Journal of Biological Chemistry

131

177

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Background: Mesencephalic astrocyte-derived neurotrophic factor is a secreted protein with an unknown mechanism of action. Results: KDEL-like sequence of MANF ("RTDL") is required for ER retention, secretory responsiveness to ER stress, and surface binding. Conclusion: KDEL receptors modulate secretion and surface binding of MANF. Significance: The plasma membrane localization of KDELRs has implications for MANF and other KDEL-containing proteins.

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A molecular specificity code for the three mammalian KDEL receptors

Cited by 218 publications

References 29 publications

The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

Dimerization of visual pigments in vivo

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

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