A single binding site for dilysine retrieval motifs and p23 within the γ subunit of coatomer

Harter, Cordula; Wieland, Felix

doi:10.1073/pnas.95.20.11649

Cited by 84 publications

(66 citation statements)

References 39 publications

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“…The trafficking phenotypes observed in a panel of ␣-and ␤Ј-COP WD40 domain mutants are consistent with this notion. Another interaction site in coatomer for di-lysine type motifs has been indicated in mammalian ␥-COP by using a photo-cross-linking approach (Harter et al, 1996;Harter and Wieland, 1998) and by in vitro binding data (Wu et al, 2000). However, this binding site must be structurally different from the binding sites on ␣-and ␤Ј-COP reported here, because ␥-COP does not harbor WD40 repeats.…”

Section: Wd40 Domains As Recognition Modules For Variants Of the Di-lmentioning

confidence: 98%

“…Thus, ␣-COP cannot be the only receptor for di-lysine tagged COP I cargo proteins in yeast (Schrö der et al, 1995;Schrö der-Kohne et al, 1998). Both photo-cross-linking data (Harter et al, 1996;Harter and Wieland, 1998) and in vitro binding data (Wu et al, 2000) have suggested that a binding site for di-lysine motifs is present on mammalian ␥-COP. An equivalent binding site has so far not been characterized in the yeast ␥-COP orthologue.…”

Section: Introductionmentioning

confidence: 99%

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The α- and β′-COP WD40 Domains Mediate Cargo-selective Interactions with Distinct Di-lysine Motifs

Eugster

Frigerio

Dale

et al. 2004

MBoC

102

107

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Coatomer is required for the retrieval of proteins from an early Golgi compartment back to the endoplasmic reticulum. The WD40 domain of ␣-COP is required for the recruitment of KKTN-tagged proteins into coatomer-coated vesicles. However, lack of the domain has only minor effects on growth in yeast. Here, we show that the WD40 domain of ␤ -COP is required for the recycling of the KTKLL-tagged Golgi protein Emp47p. The protein is degraded more rapidly in cells with a point mutation in the WD40 domain of ␤ -COP (sec27-95) or in cells lacking the domain altogether, whereas a point mutation in the Clathrin Heavy Chain Repeat (sec27-1) does not affect the turnover of Emp47p. Lack of the WD40 domain of ␤ -COP has only minor effects on growth of yeast cells; however, absence of both WD40 domains of ␣-and ␤ -COP is lethal. Two hybrid studies together with our analysis of the maturation of KKTN-tagged invertase and the turnover of Emp47p in ␣-and ␤ -COP mutants suggest that the two WD40 domains of ␣-and ␤ -COP bind distinct but overlapping sets of di-lysine signals and hence both contribute to recycling of proteins with di-lysine signals.

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Section: Wd40 Domains As Recognition Modules For Variants Of the Di-lmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

The α- and β′-COP WD40 Domains Mediate Cargo-selective Interactions with Distinct Di-lysine Motifs

Eugster

Frigerio

Dale

et al. 2004

MBoC

102

107

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“…The COPI complex (Duden et al, 1991;Waters et al, 1991;Rothman, 1994) is known to bind the dilysine motif through ␥-COP (Harter et al, 1996;Harter and Wieland, 1998). A ␥-COP homolog from Arabidopsis, AtSec21p, has been cloned recently and partially characterized (Movafeghi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The retrieval mechanism is mediated by vesicular Golgi apparatus-to-ER retrograde transport, involving the coat protein I (COPI) complex (Cosson and Letourneur, 1994;Letourneur et al, 1994;Cosson et al, 1996). The dilysine motif interacts directly with COPI, which then drives the recycling of type I membrane proteins to the ER (Cosson and Letourneur, 1994;Letourneur et al, 1994;Cosson et al, 1996;Harter et al, 1996;Kappeler et al, 1997;Harter and Wieland, 1998). A recent study has also demonstrated that the KKAA motif of a chimeric reporter protein is localized in the ER by a retention mechanism, because it does not acquire any of the cis -Golgi apparatus modifications it would have if it were cycling from the ER to the Golgi apparatus and back to the ER (Andersson et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

The C-Terminal Dilysine Motif Confers Endoplasmic Reticulum Localization to Type I Membrane Proteins in Plants

2000

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The tomato Cf-9 disease resistance gene encodes a type I membrane protein carrying a cytosolic dilysine motif. In mammals and yeast, this motif promotes the retrieval of type I membrane proteins from the Golgi apparatus to the endoplasmic reticulum (ER). To test whether the C-terminal KKXX signal of Cf-9 is functional as a retrieval motif and to investigate its role in plants, green fluorescent protein (GFP) was fused to the transmembrane domain of Cf-9 and expressed in yeast, Arabidopsis, and tobacco cells. The fusion protein was targeted to the ER in each of these expression systems, and mutation of the KKXX motif to NNXX led to secretion of the fusion protein. In yeast, the mutant protein reached the vacuole, but plants secreted it as a soluble protein after proteolytic removal of the transmembrane domain. Triple hemagglutinin (HA)-tagged full-length Cf-9 was also targeted to the ER in tobacco cells, and cleavage was also observed for the NNXX mutant protein, suggesting an endoprotease recognition site located within the Cf-9 lumenal sequence common to both the GFP-and the HA-tagged fusions. Our results indicate that the KKXX motif confers ER localization in plants as well as mammals and yeast and that Cf-9 is a resident protein of the ER. INTRODUCTIONProteins resident in the endoplasmic reticulum (ER) contain structural motifs responsible for their correct subcellular localization. Many soluble ER proteins, such as BiP or protein disulfide isomerase, carry a C-terminal tetrapeptide H/KDEL motif for localization in the ER (Munro and Pelham, 1987;Pelham et al., 1988;Mazzarella et al., 1990;Andres et al., 1991; Denecke et al., 1992 Denecke et al., , 1993Napier et al., 1992). A membrane-bound receptor encoded by the yeast ERD2 gene retrieves escaping HDEL-marked proteins from the Golgi apparatus or salvage compartment back to the ER Semenza et al., 1990). Homologs of the Erd2 receptor have been cloned from mammals Pelham, 1990, 1992; Tang et al., 1993) and plants ( Lee et al., 1993), highlighting conservation of the H/KDEL motif and retrieval mechanism.In mammals and yeast, the cytosolic dilysine motif is critical for ER localization of type I membrane proteins (Nilsson et al., 1989;Jackson et al., 1990). The two lysine residues need to be in either the Ϫ 3, Ϫ 4 (KKXX) or Ϫ 3, Ϫ 5 (KXKXX) positions relative to the C terminus, and no other basic amino acid can be substituted (Jackson et al., 1990(Jackson et al., , 1993. Mutation of lysine residues leads to expression of the reporter protein on the cell surface in mammals (Nilsson et al., 1989;Jackson et al., 1990) and to its vacuolar delivery in yeast (Gaynor et al., 1994). Studies of the post-translational modification kinetics of dilysine-tagged reporter proteins have demonstrated a constant cycling of the reporter from the ER to the Golgi apparatus and back to the ER (Jackson et al., 1993;Gaynor et al., 1994). The retrieval mechanism is mediated by vesicular Golgi apparatus-to-ER retrograde transport, involving the coat protein I (COPI) complex (Cosson and...

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“…2B). The small amount of residual A␤ produced in the cells overexpressing SwAPP-(KKQN) could be related to incomplete retention of the protein in the ER, possibly due to saturation of coatomer binding sites (82). Alternatively, it could reflect the presence of ␥-secretase activity in the ER, possibly allowing a small pool of SwAPP to be transported to the ␤-secretase compartment after removal of the C-terminal tail containing the KKQN motif.…”

Section: Retention Of the App C99 Domain In The Er Decreases The Prodmentioning

confidence: 99%

Retention of the Alzheimer's Amyloid Precursor Fragment C99 in the Endoplasmic Reticulum Prevents Formation of Amyloid β-Peptide

Maltese

Wilson

Tan³

et al. 2001

Journal of Biological Chemistry

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␥-Secretase is a membrane-associated endoprotease that catalyzes the final step in the processing of Alzheimer's ␤-amyloid precursor protein (APP), resulting in the release of amyloid ␤-peptide (A␤). The molecular identity of ␥-secretase remains in question, although recent studies have implicated the presenilins, which are membrane-spanning proteins localized predominantly in the endoplasmic reticulum (ER). Based on these observations, we have tested the hypothesis that ␥-secretase cleavage of the membrane-anchored C-terminal stump of APP (i.e. C99) occurs in the ER compartment. When recombinant C99 was expressed in 293 cells, it was localized mainly in the Golgi apparatus and gave rise to abundant amounts of A␤. Co-expression of C99 with mutant forms of presenilin-1 (PS1) found in familial Alzheimer's disease resulted in a characteristic elevation of the A␤ 42 /A␤ 40 ratio, indicating that the N-terminal exodomain of APP is not required for mutant PS1 to influence the site of ␥-secretase cleavage. Biogenesis of both A␤ 40 and A␤ 42 was almost completely eliminated when C99 was prevented from leaving the ER by addition of a di-lysine retention motif (KKQN) or by co-expression with a dominant-negative mutant of the Rab1B GTPase. These findings indicate that the ER is not a major intracellular site for ␥-secretase cleavage of C99. Thus, by inference, PS1 localized in this compartment does not appear to be active as ␥-secretase. The results suggest that presenilins may acquire the characteristics of ␥-secretase after leaving the ER, possibly by assembling with other proteins in peripheral membranes.Amyloid ␤-peptide (A␤) 1 is the major molecular component of the cerebral amyloid plaques associated with Alzheimer's disease. The cellular pathways involved in the biogenesis of A␤ have been the subject of intense investigation since the discovery that A␤ originates from intracellular endoproteolytic processing of a type I membrane-spanning glycoprotein termed amyloid precursor protein (APP) (1-4). Extensive studies have established that APP can be processed via two alternative routes, one of which yields the 4-kDa A␤, whereas the other yields a truncated non-amyloidogenic peptide (p3) (5, 6). In most cells the non-amyloidogenic pathway predominates. The first step involves the cleavage of APP within the A␤ domain by a protease termed ␣-secretase (7-9). After release of the Nterminal exodomain, the residual 83-amino acid membranespanning C-terminal fragment is further processed by another protease termed ␥-secretase to remove the cytoplasmic tail and generate p3 (6, 10). Because the latter cleavage occurs within the predicted membrane spanning region of APP (11-13), ␥-secretase is generally thought to be an intramembrane protease. In the alternative amyloidogenic pathway, APP is initially cleaved proximal to the A␤ sequence by ␤-secretase, leaving a 99-amino acid C-terminal fragment (C99) that contains the intact A␤ sequence and the cytoplasmic tail (1,14,15). Thus, when ␥-secretase cuts the latter substrate, A␤ is rel...

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A single binding site for dilysine retrieval motifs and p23 within the γ subunit of coatomer

Cited by 84 publications

References 39 publications

The α- and β′-COP WD40 Domains Mediate Cargo-selective Interactions with Distinct Di-lysine Motifs

The α- and β′-COP WD40 Domains Mediate Cargo-selective Interactions with Distinct Di-lysine Motifs

The C-Terminal Dilysine Motif Confers Endoplasmic Reticulum Localization to Type I Membrane Proteins in Plants

Retention of the Alzheimer's Amyloid Precursor Fragment C99 in the Endoplasmic Reticulum Prevents Formation of Amyloid β-Peptide

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