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.20070518020080116c

Cited by 30 publications

(53 citation statements)

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“…Unlike most other members of the PDI family, AGR3 lacks the canonical C XX C active‐site motif; instead, it has the CYQS sequence, suggesting that it is not involved in thiol–disulphide exchange in protein folding. AGR3 has an ER retention signal QSEL in C‐terminal and is retained in the ER via its C‐terminal motif [Raykhel et al., ]. AGR3 is expressed in the ciliated cells of the airway epithelium and oviduct as well as in the stomach, prostate and liver [Bonser et al., ; Obacz et al., ].…”

Section: Other Human Agr Proteinsmentioning

confidence: 99%

The role of protein disulphide isomerase AGR2 in the tumour niche

Delom

Nazaraliyev

Fessart

2018

Biology of the Cell

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In recent years, the discovery of 'tumour niche', a microenvironment that favours tumour development has changed our perspective of cancer. This microenvironment generated by the tumour cells itself and surrounding cells is capable of providing essential elements for its growth. Consequently, the homoeostasis of the secretory pathway (SP) has become an essential player in cancer development. The SP not only promotes cellular adaptation to protein misfolding due to oncogenic transformation or challenging tumour niche but also allows tumour cells to produce specific secretomes. This impacts tumour cells in cis-or trans-as well as stromal cells in the tumour niche. In this context, the Anterior GRadient 2 (AGR2) protein has been identified as a key player. AGR2 is a protein disulphide isomerase that resides in the endoplasmic reticulum (ER) and mediates the formation of disulphide bonds, catalyses the cysteine-based redox reactions and assists the quality control of proteins. AGR2 not only plays an essential role in the homoeostasis of the SP but also exerts pro-oncogenic gain-of-function due to its reported mislocalisation in the tumour niche microenvironment. In this review, we summarise the dual role of AGR2, inside and outside the ER, on the tumour niche and its microenvironment.

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Section: Other Human Agr Proteinsmentioning

confidence: 99%

The role of protein disulphide isomerase AGR2 in the tumour niche

Delom

Nazaraliyev

Fessart

2018

Biology of the Cell

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“…The finding that KDEL‐proteins can be modified by post‐ER enzymes indicated that these proteins are retrieved from Golgi cisternae [89,90]. Genetic screens in yeast identified ERD2 as the receptor mediating the retrieval of KDEL‐proteins (KDELR) [46], and orthologues have since been characterized in vertebrates, including three human isoforms [91–93]. Vectorial transport of KDEL‐proteins was suggested to exploit pH differences between the Golgi and the ER [94].…”

Section: Cargo Sortingmentioning

confidence: 99%

“…In humans, a distinction between the various signals is achieved by differential specificities of the three KDELRs. Although some overlap exists, it appears that each KDEL receptor mediates the retrieval of a subgroup of soluble ER proteins [93].…”

Section: Cargo Sortingmentioning

confidence: 99%

The COPI system: Molecular mechanisms and function

et al. 2009

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a b s t r a c tTransport of membranes and proteins in eukaryotic cells is mediated by vesicular carriers. Here we review the biogenesis and functions of COPI vesicles, carriers that operate in the early secretory pathway. We focus on mechanisms mediating coat recruitment, uptake of cargo, vesicle budding and fission, and finally dissociation of the coat. In this context, recent findings on the interplay between machinery and auxiliary proteins in COPI vesicle formation and function will be discussed. Specifically, we will weigh the pros and cons of recent data on roles of the small GTP binding protein Arf1, of Arf1GAPs, and lipids during COPI carrier formation.

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“…Mechanisms, although poorly characterized to date, must exist to eliminate excess H 2 O 2 in the ER. In mammalian cells, various peroxidases are distributed in the cytosol, nucleus and mitochondria, but only three, Prx (peroxiredoxin) 4 [4] and two GPx (glutathione peroxidase) homologues, GPx7 and GPx8 [5], have been reported to be located in the ER to date.…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the peroxidase activity and inactivation of human peroxiredoxin 4

Wang

Sun

et al. 2011

Biochemical Journal

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Prx4 (peroxiredoxin 4) is the only peroxiredoxin located in the ER (endoplasmic reticulum) and a proposed scavenger for H2O2. In the present study, we solved crystal structures of human Prx4 in three different redox forms and characterized the reaction features of Prx4 with H2O2. Prx4 exhibits a toroid-shaped decamer constructed of five catalytic dimers. Structural analysis revealed conformational changes around helix α2 and the C-terminal reigon with a YF (Tyr-Phe) motif from the partner subunit, which are required for interchain disulfide formation between Cys87 and Cys208, a critical step of the catalysis. The structural explanation for the restricting role of the YF motif on the active site dynamics is provided in detail. Prx4 has a high reactivity with H2O2, but is susceptible to overoxidation and consequent inactivation by H2O2. Either deletion of the YF motif or dissociation into dimers decreased the susceptibility of Prx4 to overoxidation by increasing the flexibility of Cys87.

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A molecular specificity code for the three mammalian KDEL receptors

Cited by 30 publications

References 0 publications

The role of protein disulphide isomerase AGR2 in the tumour niche

The role of protein disulphide isomerase AGR2 in the tumour niche

The COPI system: Molecular mechanisms and function

Structural insights into the peroxidase activity and inactivation of human peroxiredoxin 4

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