GGA Autoinhibition Revisited

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GGA Autoinhibition Revisited Traffic 2010; 11: 259–273 © 2009 John Wiley & Sons A/S doi:10.1111/j.1600-0854.2009.01017.x GGA Autoinhibition Revisited Jacob F. Cramer1, Camilla Gustafsen2,ManjaA. GGAs contain separate functional sites that facilitate their Behrens3, Cristiano L. P. Oliveira3, Jan Skov binding to membranes, accessory proteins, clathrin and specific sorting motifs in the cytoplasmic domains of Pedersen3, Peder Madsen2, Claus Munck transmembrane cargo proteins (1–5). In GGAs, however, 2,∗ 1,∗ Petersen and Søren S. Thirup the molecular functions relate to a conserved modular organization of a single chain and not to individual subunits 1MIND Centre, Department of Molecular Biology, Aarhus as seen in the AP complexes (reviewed in 6). From the University, Gustav Wieds Vej 10 C, DK-8000 Aarhus C, N-terminus, each GGA contains a VHS domain (Vps27, Denmark Hrs, Stam; ∼140 residues), a 20 residues linker sequence 2MIND Centre, Department of Medical Biochemistry, which is followed by a GAT domain (GGA and TOM; Aarhus University, Ole Worms Alle´ 1170, DK-8000 ∼150 residues), a variable presumably unstructured 80- Aarhus C, Denmark 286 residue hinge region and finally a C-terminal GAE 3 Department of Chemistry and iNANO Interdisciplinary domain (γ-adaptin ear) (Figure 1A). Whereas binding of Nanoscience Center, Aarhus University, Langelandsgade accessory proteins, clathrin and membrane-associated 140, DK-8000 Aarhus C, Denmark Arf-GTP is accounted for by the GAE domain (7–9), the *Corresponding authors: Søren S. Thirup and Claus hinge regions and the GAT domain (10,11), respectively, Munck Petersen the VHS domain is responsible for binding of the cargo [email protected], [email protected] proteins (12–15). The cytosolic adaptors GGA1-3 mediate sorting of Although the role(s) of GGAs is far from clarified, it seems transmembrane proteins displaying a C-terminal acidic clear that they contribute, alone or in cooperation with dileucine motif (DXXLL) in their cytosolic domain. GGA1 other adaptors like AP-1 and phosphofurin acidic cluster and GGA3 contain similar but intrinsic motifs that are sorting protein 1 (PACS1), to the sorting and transport believed to serve as autoinhibitory sites activated by the phosphorylation of a serine positioned three residues of receptors between the trans Golgi network (TGN) upstream of the DXXLL motif. In the present study, and endosomal compartments (16). This is underscored we have subjected the widely acknowledged concept by the fact that most of the six identified GGA-binding of GGA1 autoinhibition to a thorough structural and cargo proteins are known to be active in Golgi-endosome functional examination. We find that (i) the intrinsic trafficking. The cargo proteins include the Vps10p- motif of GGA1 is inactive, (ii) only C-terminal DXXLL domain receptors Sortilin (12,14) and SorLA (17,18), motifs constitute active GGA binding sites, (iii) while the cation-independent (13–15) (CI) and the cation- aspartates and phosphorylated serines one or two dependent (13,19) (CD) mannose 6-phosphate receptors positions upstream of the DXXLL motif increase GGA1 (MPRs), the low-density lipoprotein-related protein 3 binding, phosphoserines further upstream have little or (LRP3) (14) and BACE (β-site amyloid precursor protein no influence and (iv) phosphorylation of GGA1 does not cleaving enzyme, β-secretase) (20), and each of these affect its conformation or binding to Sortilin and SorLA. Taken together, our findings seem to refute the functional are characterized by having an ’acidic-cluster dileucine’ significance of GGA autoinhibition in particular and of type motif close to the C-terminus of their cytoplasmic intrinsic GGA binding motifs in general. domain. This motif forms the basis for interaction with the VHS domain of GGAs that have been directed to Key words: acidic cluster dileucine, GGA, VHS domain, the membrane via GAT domain-mediated binding to ARF- phosphorylation, autoinhibition, sortilin, SorLA, x-ray GTP (10). Studies by several groups and implementation of structure various techniques, including yeast two-hybrid and crystal structure analysis, have established that the sequence Received 27 April 2009, revised and accepted for DXXLL (where X could be any residue and M or V could publication 4 November 2009, uncorrected manuscript substitute for L) forms the minimal requirements for GGA published online 10 November 2009, published online 11 binding (19,21–24). However, in addition to the essential December 2009 aspartate (position 0) and dileucine (positions +3and +4), nearby residues both upstream and downstream to the signal are known to modulate the interaction. The Golgi-localized, γ-ear-containing, Arf-binding proteins In the first place, one or more upstream aspartates (GGAs) constitute a family of three (GGA1-3) monomeric and/or phosphorylatable serines are found in all the target adaptor proteins (APs) that are ubiquitously expressed. proteins, and an additional Asp or phosphorylated Ser The GGAs contribute to the formation of coats on the (pS) at position -1 results in a significant increase in cytosolic face of vesicular transport carriers and to the the affinity for VHS-domain binding (25). An effect of D selection and incorporation of specific cargo proteins into or pS at positions -2 and -3, on the other hand, has the carriers. Like the tetraheteromeric AP complexes, not been convincingly demonstrated. Second, previous www.traffic.dk 259 Cramer et al. in position -3, the hinge site becomes activated and each of the two adaptors binds their respective VHS domain and undergoes a conformational change (27). Thus, the unphosphorylated adaptor is stated to contain a free VHS domain, which enables it to bind and sort its transmembrane targets, whereas the phosphorylated adaptor is inaccessible to cargo proteins as it engages and inhibits its own VHS domain. Previous reports suggest that the resulting mechanism of regulated autoinhibition may play an important role in the orchestration of AP-1, PACS1 and GGA-mediated Golgi-endosome sorting of cargo such as MPRs and Sortilin (28,29). In the present study, we have taken a closer look at GGA autoinhibition using peptides and full-length proteins. We have studied the interaction between GGA1, its intrinsic VHS binding site and its transmembrane targets Sortilin and SorLA and have focused on the role of phosphorylatable serines and C-terminal requirements of the binding motifs. Our findings are incompatible with the existence of a functional intrinsic VHS-binding motif and the concept of GGA1 autoinhibition. Results To examine the interaction between GGA1 and estab- lished DXXLL motifs, we initially generated a series of peptides derived from the VHS-domain binding C-termini of Sortilin and SorLA, and from the intrinsic ‘autoinhibitory’ site in the hinge region of GGA1 itself. The peptides include unmodified sequences (designated So, Sa and Hi, respectively) as well as phosphorylated (SoP, SaP, HiP), Figure 1: Schematic representation of GGA structure and point mutated and extended peptides (Figure 1B). DXXLL peptides. A) The structure of GGA1 with proteins that bind to each domain indicated by arrows and the autoinhibitory For reference, we first determined the structures of the sequences of GGA1 and GGA3 shown together with the DXXLL unmodified peptides in complex with the GGA1-VHS motif of Sortilin, SorLA, CI- and CD-MPR, LRP3, LRP9 and BACE. domain. The structures of VHS:So and VHS:Sa were The three critical residues in the DXXLL motif are marked by grey determined at 2.3 and 1.7 A,˚ respectively. As can be and serine residues that are potential targets for phosphorylation seen (Figure 2A–D), the seven C-terminal residues of are marked by red. B) Sequence of DXXLL peptides from GGA1, So and the eight C-terminal residues of Sa are clearly Sortilin, SorLA and LRP9 used in this study. defined in the electron density and firmly bound in the depression between helices α6andα8 of the VHS domain. findings have strongly indicated that whereas one or Notably, both peptides are anchored by tight positioning two C-terminal residues (positions +5and+6) may of the three key residues, i.e. the aspartate at position 0 help to stabilize the interaction, additional C-terminal and the ‘dileucine’ at position 3-4. Thus, the sites in residues may actually abrogate the signal and abolish Sortilin and SorLA bind GGA1 in accordance with previous binding (19,22). In other words, the GGA-binding motif is observations on similar complexes involving the signal β only active when found at the extreme C-terminus of the peptides of the MPRs and the -secretase BACE (22–24). cytoplasmic domain. A more detailed description of the two structures is found as supplementary material. In light of this, it is obviously surprising that the GGAs themselves have been reported to contain functional Only phosphoserines immediately upstream to the intrinsic DXXLL sites for VHS-domain binding (Figure 1A; DXXLL motif contribute to VHS-domain complex 26). The sites are located in the hinge region of GGA1 formation and 3, but not in GGA2, and both GGAs are supposed Each of the three peptides So, Sa and Hi contains to exhibit regulated autoinhibition by binding their own a single upstream phosphorylatable serine found at VHS domain (26). The native proteins show no intrinsic positions -1 (So), -2 (Sa) or -3 (Hi). To investigate if binding but following phosphorylation of a serine residue and how phosphorylation of these serines could facilitate 260 Traffic 2010; 11: 259–273 GGA Revisited Figure 2: Interaction between the GGA1-VHS domain and DXXLL peptides from Sortilin and SorLA. A and B) Overall architecture of the VHS:So (Sortilin) and VHS:Sa (SorLA) complex, respectively, with the VHS domain shown by surface representation and the bound DXXLL peptide molecule as a ’ball-and-stick’ model coloured by atom type (nitrogen, blue; carbon, yellow; oxygen, red). The two helices, α6andα8, are shown together with side chains that form the binding pocket at the VHS surface (grey, transparent).
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