New COP1-binding motifs involved in ER retrieval

Cosson, Pierre; Lefkir, Yaya; Démollière, Corinne; Letourneur, François

doi:10.1093/emboj/17.23.6863

Cited by 75 publications

(55 citation statements)

References 32 publications

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“…This observation is in line with the fact that a third yeast protein proposed as a tryptophan-based motif containing δ-COP MHD ligand, originally termed "δL" and now named "Cex1p" (14), has a mammalian homolog, Scyl1, that now has been shown to be a cytosolic protein implicated in Golgi-to-ER transport (26). Because binding of similar strength can be detected to WxxxxW, WxxxxxW, and WxxxxxxW constructs ( Fig.…”

Section: Discussionsupporting

confidence: 74%

“…Cassel and coworkers (13) have demonstrated, for mammalian ArfGAP1, that a di-tryptophan motif (WxxxxW) located within the unstructured C terminus of the protein can bind to the mammalian δ-COP C-terminal μ-homology domain (MHD). Intriguingly, this tryptophan motif resembles a proposed yeast δ-COP-binding motif termed "δL," which was identified by yeast two-hybrid screening and then discovered in a cytosolic protein which at that time was of uncertain function in COPI vesicle trafficking (14). Subsequently similar motifs were identified in the central low complexity region (the so-called "lasso") of the Dsl1p subunit of the yeast Dsl1 tethering complex (7)(8)(9)15).…”

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confidence: 78%

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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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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 78%

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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“…A closer look at the Dsl1p primary structure revealed the presence of a ␦-COP binding motif (␦L) that has been characterized before by Cosson et al (7). The spacing of two tryptophans and the composition of surrounding residues resemble that of the ␦L motif.…”

Section: Dsl1pmentioning

confidence: 69%

Dsl1p, an Essential Component of the Golgi-Endoplasmic Reticulum Retrieval System in Yeast, Uses the Same Sequence Motif to Interact with Different Subunits of the COPI Vesicle Coat

Andag

Schmitt

2003

Journal of Biological Chemistry

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Dsl1p is required for Golgi-endoplasmic reticulum (ER) retrograde transport in yeast. It interacts with the ER resident protein Tip20p and with ␦-COP, a subunit of coatomer, the coat complex of COPI vesicles. To test the significance of these interactions, we mapped the different binding sites and created mutant versions of Dsl1p and ␦-COP, which are unable to bind directly to each other. Three domains were identified in Dsl1p: a Tip20p binding region within the N-terminal 200 residues, a highly acidic region in the center of Dsl1p containing crucial tryptophan residues that is required for binding to ␦-COP and essential for viability, and an evolutionarily well conserved domain at the C terminus. Most importantly, Dsl1p uses the same central acidic domain to interact not only with ␦-COP but also with ␣-COP. Strong interaction with ␣-COP requires the presence of comparable amounts of ⑀-COP or ␤-COP. Thus, the binding characteristics of Dsl1p resemble those of many accessory factors of the clathrin coat. They interact with different layers of the vesicle coat by using tandemly arranged sequence motifs, some of which have dual specificity.The structural integrity of membrane-bound organelles requires the recycling of lipids and proteins. Between Golgi and the endoplasmic reticulum (ER) 1 this retrograde transport is mediated by COPI-coated vesicles (1). The COPI coat from yeast and mammals consists of seven COP proteins (␣-, ␤Ј-, ␤-, ␥-, ␦-, ⑀-, and -COP ϭ coatomer) and the small GTPase ARF1 (2, 3). Sorting of cargo proteins to COPI vesicles can be achieved by direct binding of cargo molecules to coatomer (4 -8). This binding is often mediated by short sequence motifs displayed by cargo molecules (6, 9). The efficient sorting of cargo into COPI vesicles depends on GTP hydrolysis by ARF1 facilitated by a specific GTPase-activating proteins (10).After the uncoating, vesicles are ready to fuse with their specific target membrane (11). Fusion events rely on specific attachment reactions to guarantee that only appropriate membranes can mix. The membrane attachment itself comprises two steps, tethering and docking (12). Both steps involve different sets of proteins. Tethering factors are peripherally membrane-associated protein complexes consisting of up to 10 different subunits, which share little sequence similarity. So far, seven different tethering complexes required for at least five different transport steps were characterized in yeast (13)(14)(15)(16)(17)(18)(19)(20). In some cases, mammalian counterparts of yeast tethering factors were identified (reviewed in Ref. 21).The subsequent docking stage involves specific sets of membrane-anchored proteins, the so-called SNARE proteins (22,23). In contrast to the tethering factors, all known SNARE proteins are members of either of three protein families: the syntaxins, the synaptobrevins or VAMPs and the SNAP-25 family members. To induce membrane fusion, SNARE proteins from apposed membranes must interact in trans. The SNARE or SNARE-like proteins involved in fusion at ...

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“…Herp also lacks a Cterminal K(X)KXX motif, facilitating the interaction of the protein with the coatomer (COP1) complex for the retrograde transport of type I membrane proteins back to the ER (33). Other motifs such as a diphenylalanine sequence (34,35), a ␦L sequence (36), and transmembrane domain structure (37)(38)(39) may act as the signal for ER retrieval or retention; the mechanism by which Herp is localized to the ER, however, remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Herp, a New Ubiquitin-like Membrane Protein Induced by Endoplasmic Reticulum Stress

Kokame

Agarwala

Kato

et al. 2000

Journal of Biological Chemistry

298

286

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Hyperhomocysteinemia, a risk factor for vascular disease, injures endothelial cells through undefined mechanisms. We previously identified several homocysteineresponsive genes in cultured human vascular endothelial cells, including the endoplasmic reticulum (ER)-resident molecular chaperone GRP78/BiP. Here, we demonstrate that homocysteine induces the ER stress response and leads to the expression of a novel protein, Herp, containing a ubiquitin-like domain at the N terminus. mRNA expression of Herp was strongly upregulated by inducers of ER stress, including mercaptoethanol, tunicamycin, A23187, and thapsigargin. The ER stress-dependent induction of Herp was also observed at the protein level. Immunochemical analyses using Herpspecific antibodies indicated that Herp is a 54-kDa, membrane-associated ER protein. Herp is the first integral membrane protein regulated by the ER stress response pathway. Both the N and C termini face the cytoplasmic side of the ER; this membrane topology makes it unlikely that Herp acts as a molecular chaperone for proteins in the ER, in contrast to GRP78 and other ER stress-responsive proteins. Herp may, therefore, play an unknown role in the cellular survival response to stress.

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New COP1-binding motifs involved in ER retrieval

Cited by 75 publications

References 32 publications

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

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

Dsl1p, an Essential Component of the Golgi-Endoplasmic Reticulum Retrieval System in Yeast, Uses the Same Sequence Motif to Interact with Different Subunits of the COPI Vesicle Coat

Herp, a New Ubiquitin-like Membrane Protein Induced by Endoplasmic Reticulum Stress

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