COPII and COPI Traffic at the ER-Golgi Interface

Szul, Tomasz; Sztul, Elizabeth

doi:10.1152/physiol.00017.2011

Cited by 117 publications

(139 citation statements)

References 204 publications

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“…The more severe phenotype observed in the LsCOPB2 knock down lice compared to LsKDELR knock down lice indicates a more essential or broader role of LsCOPB2. This is in accordance with the hypothesis that the role of KDELR is to bind and transport ER resident proteins bearing the KDEL motif back to the ER, while the COPI coat is also involved in other types of retrograde transport (Szul and Sztul, 2011). Similar to our findings, knock down of a COPI subunit in the yellow fever mosquito resulted in inhibited follicular development and blocked egg shell secretion .…”

Section: Discussionsupporting

confidence: 93%

“…Resident ER proteins interact directly with the COPI subunits, by interaction with a Vps74p linker, or by binding to the KDEL receptor (KDELR) (reviewed by Beck et al, 2009;Bethune et al, 2006;Szul and Sztul, 2011). Proteins with a C-terminal KDEL motif (HDEL in yeast) are recognized by KDELR, also known as the ER lumen retaining protein receptor (ERPR).…”

Section: Introductionmentioning

confidence: 99%

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RNA interference mediated knockdown of the KDEL receptor and COPB2 inhibits digestion and reproduction in the parasitic copepod Lepeophtheirus salmonis

Tröße

Nilsen

Dalvin

2014

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Retrograde transport of proteins from the endoplasmic reticulum to the Golgi is an essential part of the secretory pathway that all newly synthesised secreted and membrane proteins in eukaryotic cells undergo. The aim of this study was to characterise two components of the retrograde transport pathway in the parasitic copepod Lepeophtheirus salmonis (salmon louse) on a molecular and functional level. LsKDELR and LsCOPB2 were confirmed to be the salmon louse homologues of the chosen target proteins by sequence similarity. Ontogenetic analysis by qRT-PCR revealed the highest expression levels of both genes in adult females and the earliest larval stage. LsKDELR and LsCOPB2 localisation in adult females was detected by immunofluorescence and in situ hybridisation, respectively. Both LsKDELR and LsCOPB2 were found in the ovaries, the oocytes and the gut.LsKDELR and LsCOPB2 were knocked down by RNA interference in preadult females, which was confirmed by qRT-PCR. LsCOPB2 knock down lice had a significantly higher mortality and failed to develop normally, while both LsCOPB2 and LsKDELR knock down caused disturbed digestion and the absence of egg strings. This shows the potential of LsKDELR and LsCOPB2 as suitable target candidates for new pest control methods.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

RNA interference mediated knockdown of the KDEL receptor and COPB2 inhibits digestion and reproduction in the parasitic copepod Lepeophtheirus salmonis

Tröße

Nilsen

Dalvin

2014

Comparative Biochemistry and Physiology Part B: Biochemistry an

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“…S1; note, however, that the last of these binds less tightly, with a K d of ∼50 μM), the δ-COP MHDbinding motif can be redefined as Wx n (1)(2)(3)(4)(5)(6) [WF], which may aid in identifying new accessory factors for COPI-coated vesicle formation/disassembly. Our in vivo data indicate that growth defects and CPY trafficking/processing defects can be brought about by disrupting δ-COP MHD Wx n (1)(2)(3)(4)(5)(6) [WF] motif binding, but only in a sensitized system (e.g., in which the Dsl1p E-domain is deleted or Glo3p is absent). The need for multiple mutations to reveal phenotypic alterations likely reflects high levels of redundancy in this important cellular transport route, such as the binding of the other ArfGAP Glo3p by the F-subcomplex γ-COP appendage (12) and the binding of the Dsl1p lasso by α-COP (7).…”

Section: Discussionmentioning

confidence: 99%

“…After nucleotide hydrolysis and Arf1:GDP disengagement, the F-subcomplex likely would revert to a more closed form; however, because of the COPI B-subcomplex binding to KKxx and KxKxx transmembrane cargoes (29)(30)(31), the coat should not dissociate from the vesicle surface immediately (5). Assuming that the F-subcomplex adopts a closed conformation similar to that of a cytosolic AP complex, modeling suggests that the Wx n (1)(2)(3)(4)(5)(6) [WF] binding site on δ-COP should be accessible when the F-subcomplex is closed (Fig. S7).…”

Section: Discussionmentioning

confidence: 99%

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Structural basis for the binding of tryptophan-based motifs by δ-COP

Suckling

Poon

Travis

et al. 2015

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

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Coatomer consists of two subcomplexes: the membrane-targeting, ADP ribosylation factor 1 (Arf1):GTP-binding βγδζ-COP F-subcomplex, which is related to the adaptor protein (AP) clathrin adaptors, and the cargo-binding αβ'e-COP B-subcomplex. We present the structure of the C-terminal μ-homology domain of the yeast δ-COP subunit in complex with the WxW motif from its binding partner, the endoplasmic reticulum-localized Dsl1 tether. The motif binds at a site distinct from that used by the homologous AP μ subunits to bind YxxΦ cargo motifs with its two tryptophan residues sitting in compatible pockets. We also show that the Saccharomyces cerevisiae Arf GTPase-activating protein (GAP) homolog Gcs1p uses a related WxxF motif at its extreme C terminus to bind to δ-COP at the same site in the same way. Mutations designed on the basis of the structure in conjunction with isothermal titration calorimetry confirm the mode of binding and show that mammalian δ-COP binds related tryptophan-based motifs such as that from ArfGAP1 in a similar manner. We conclude that δ-COP subunits bind Wx n(1-6) [WF] motifs within unstructured regions of proteins that influence the lifecycle of COPI-coated vesicles; this conclusion is supported by the observation that, in the context of a sensitizing domain deletion in Dsl1p, mutating the tryptophan-based motif-binding site in yeast causes defects in both growth and carboxypeptidase Y trafficking/processing. C OPI vesicles mediate retrograde trafficking from the Golgi to the endoplasmic reticulum (ER) and within the Golgi (reviewed in refs. 1-3). The COPI vesicle coat consists of two major components, coatomer and the small GTPase ADP ribosylation factor 1 (Arf1). Coatomer is an ∼600 kDa heteroheptameric complex consisting of two linked subcomplexes, the βγδζ-COP F-subcomplex and the αβ'e-COP B-subcomplex, all conserved from yeast to humans.Recent studies have led to a model for COPI-coated vesicle formation in which the F-subcomplex functions as a traditional Arf1:GTP effector but with two membrane-attached Arf1:GTP molecules binding to quasi-equivalent sites on a single F-subcomplex, recruiting F-subcomplex and its associated B-subcomplex onto the membrane en bloc (4). Once the vesicle has budded from its donor membrane, an Arf GTPase-activating protein (ArfGAP) catalyzes the hydrolysis of GTP on Arf1, and the Arf1:GDP dissociates from the membrane, followed later by the dissociation of the coatomer complex that was bound to the transport vesicle (5). ArfGAPs also have been proposed to function at different stages in vesicle biogenesis, both as terminators and, during an earlier cargoediting step, as effectors (reviewed in depth in ref. 6). In the final stages of its life, a COPI-coated vesicle docks with the ER via the Dsl1-tethering complex, completes uncoating, and finally undergoes SNARE-mediated fusion with the ER (7-9).The two main ArfGAPs associated with COPI-dependent retrograde transport in yeast are Gcs1p and Glo3p. These proteins can substitute for one another, at least partially,...

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Multiomics characterization of mesenchymal stromal cells cultured in monolayer and as aggregates

Doron

Klontzas

Mantalaris

et al. 2020

Biotech & Bioengineering

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Mesenchymal stromal cells (MSCs) have failed to consistently demonstrate their therapeutic efficacy in clinical trials, due in part to variability in culture conditions used for their production. Of various culture conditions used for MSC production, aggregate culture has been shown to improve secretory capacity (a putative mechanism of action in vivo) compared with standard monolayer culture. The purpose of this study was to perform multiomics characterization of MSCs cultured in monolayer and as aggregates to identify aspects of cell physiology that differ between these culture conditions to begin to understand cellular‐level changes that might be related to secretory capacity. Targeted secretome characterization was performed on multiple batches of MSC‐conditioned media, while nontargeted proteome and metabolome characterization was performed and integrated to identify cellular processes differentially regulated between culture conditions. Secretome characterization revealed a reduction in MSC batch variability when cultured as aggregates. Proteome and metabolome characterization showed upregulation of multiple protein and lipid metabolic pathways, downregulation of several cytoskeletal processes, and differential regulation of extracellular matrix synthesis. Integration of proteome and metabolome characterization revealed individual lipid metabolites and vesicle‐trafficking proteins as key features for discriminating between culture conditions. Overall, this study identifies several aspects of MSC physiology that are altered by aggregate culture. Further exploration of these processes and pathways is needed to determine their potential role in regulating cell secretory capacity.

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COPII and COPI Traffic at the ER-Golgi Interface

Cited by 117 publications

References 204 publications

RNA interference mediated knockdown of the KDEL receptor and COPB2 inhibits digestion and reproduction in the parasitic copepod Lepeophtheirus salmonis

RNA interference mediated knockdown of the KDEL receptor and COPB2 inhibits digestion and reproduction in the parasitic copepod Lepeophtheirus salmonis

Structural basis for the binding of tryptophan-based motifs by δ-COP

Multiomics characterization of mesenchymal stromal cells cultured in monolayer and as aggregates

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