Structural Basis for Recruitment and Activation of the AP-1 Clathrin Adaptor Complex by Arf1

Ren, Xuefeng; Farı́as, Ginny G.; Canagarajah, Bertram; Bonifacino, Juan S.; Hurley, James H.

doi:10.1016/j.cell.2012.12.042

Cited by 176 publications

(262 citation statements)

References 55 publications

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“…Our findings allow us to demonstrate the conservation of the canonical YXXØ binding site and thus the generality of the signal-recognition mode first shown for 2 (20). Biochemical and structural analyses indicate that 1 (A and B isoforms) (7,22,45) and 4 (12) are likely to have a similar binding site (21,22,30,(45)(46)(47), but this remains to be definitively established by x-ray crystallographic studies of 1 and 4 in complex with canonical YXXØ signals. It also remains to be determined whether 1, 2, and 3 have a second site similar to that binding YX(FYL)(FL)E signals in 4 (21).…”

Section: Resultsmentioning

confidence: 90%

Structural Basis for the Recognition of Tyrosine-based Sorting Signals by the μ3A Subunit of the AP-3 Adaptor Complex

Mardones

Burgos

Lin

et al. 2013

Journal of Biological Chemistry

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Background: Tyrosine-based, YXXØ-type signals mediate protein sorting through binding to adaptor subunits. Results: X-ray crystallography shows how YXXØ signals bind to the immunoglobulin-like fold of 3A. Conclusion: The binding site for YXXØ signals on 3A is similar to that of 2 but distinct from that of 4. Significance: The study explains the basis for the recognition of diverse YXXØ signals by subunits.

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Section: Resultsmentioning

confidence: 90%

Structural Basis for the Recognition of Tyrosine-based Sorting Signals by the μ3A Subunit of the AP-3 Adaptor Complex

Mardones

Burgos

Lin

et al. 2013

Journal of Biological Chemistry

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“…Determinants within the γ and β1 subunits are thought to define the membrane localization of AP-1 (Austin et al, 2002;Heldwein et al, 2004;Ren et al, 2013;Wang et al, 2003). Therefore, we speculate that γ1 and γ2 may mediate recruitment of AP-1 variants to distinct locations within cells.…”

Section: Discussionmentioning

confidence: 99%

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

Tavares

Silva

Silva-Januário

et al. 2017

Journal of Cell Science

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The HIV accessory protein Nef is a major determinant of viral pathogenesis that facilitates viral particle release, prevents viral antigen presentation and increases infectivity of new virus particles. These functions of Nef involve its ability to remove specific host proteins from the surface of infected cells, including the CD4 receptor. Nef binds to the adaptor protein 2 (AP-2) and CD4 in clathrin-coated pits, forcing CD4 internalization and its subsequent targeting to lysosomes. Herein, we report that this lysosomal targeting requires a variant of AP-1 containing isoform 2 of γ-adaptin (AP1G2, hereafter γ2). Depletion of the γ2 or μ1A (AP1M1) subunits of AP-1, but not of γ1 (AP1G1), precludes Nef-mediated lysosomal degradation of CD4. In γ2-depleted cells, CD4 internalized by Nef accumulates in early endosomes and this alleviates CD4 removal from the cell surface. Depletion of γ2 also hinders EGFR-EGF-complex targeting to lysosomes, an effect that is not observed upon γ1 depletion. Taken together, our data provide evidence that the presence of γ1 or γ2 subunits delineates two distinct variants of AP-1 complexes, with different functions in protein sorting.

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“…However, the open form of F-subcomplexes attached to a membrane in a coat recently has been demonstrated to be even more extreme than the open conformation of AP complexes (27,28) and now is referred to as "hyper-open" (29). The hyper-open conformation of coatomer, in which δ-COP MHD is on the very outside of the coat away from the membrane, would be maintained in the vesicle coat as long as coatomer was bound to Arf1:GTP.…”

Section: Discussionmentioning

confidence: 99%

“…By analogy with AP2 and AP1 (21,27,28), membrane recruitment of the coatomer might be expected to trigger an Arf1: GTP-driven conformational change in the F-subcomplex from an inactive closed form to an open form (4). However, the open form of F-subcomplexes attached to a membrane in a coat recently has been demonstrated to be even more extreme than the open conformation of AP complexes (27,28) and now is referred to as "hyper-open" (29).…”

Section: Discussionmentioning

confidence: 99%

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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Structural Basis for Recruitment and Activation of the AP-1 Clathrin Adaptor Complex by Arf1

Cited by 176 publications

References 55 publications

Structural Basis for the Recognition of Tyrosine-based Sorting Signals by the μ3A Subunit of the AP-3 Adaptor Complex

Structural Basis for the Recognition of Tyrosine-based Sorting Signals by the μ3A Subunit of the AP-3 Adaptor Complex

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

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

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