The Structure and Function of GGAs, the Traffic Controllers at the TGN Sorting Crossroads

Abstract

ABSTRACT. GGAs (Golgi-localizing, g-adaptin ear homology domain, ARF-binding proteins) are a family of monomeric clathrin adaptor proteins that are conserved from yeasts to humans. Data published during the past four years have provided detailed pictures of the localization, domain organization and structure-function relationships of GGAs. GGAs possess four conserved functional domains, each of which interacts with cargo proteins including mannose 6-phosphate receptors, the small GTPase ARF, clathrin, or accessory proteins including Rabaptin-5 and g-synergin. Together with or independent of the adaptor protein complex AP-1, GGAs regulate selective transport of cargo proteins, such as mannose 6-phosphate receptors, from the trans-Golgi network to endosomes mediated by clathrin-coated vesicles.

Recruitment of Tom1L1/Srcasm to Endosomes and the Midbody by Tsg101

“…Like Tom1 and GGAs, Tom1L1 interacts with ubiquitin through the GAT domain (Bonifacino, 2004;Katoh et al, 2004;Nakayama and Wakatsuki, 2003;Shiba et al, 2004;Yamakami et al, 2003) and, like Tom1, with clathrin through the C-terminal region (Colilin et al, 2007;Katoh et al, 2006;Katoh et al, 2004;Yamakami et al, 2003). In the MVB pathway, ubiquitin functions as a sorting signal for degradation; ubiquitinated cargo proteins, such as the EGF receptor, are recognized by Hrs and sorted into the MVB by sequentially interacting with ESCRT complexes, including Tsg101-containing ESCRT-I (Piper and Katzmann, 2007;Slagsvold et al, 2006;Williams and Urbé, 2007).…”

“…The GAT domain of both the GGA (Golgi-localizing, γ-adaptin ear domain homology, Arf-binding protein) and Tom1 family proteins was shown to bind ubiquitin (Bonifacino, 2004;Nakayama and Wakatsuki, 2003), suggesting their implication in sorting of ubiquitinated proteins to the MVB pathway (Katoh et al, 2006;Katoh et al, 2004;Puertollano and Bonifacino, 2004;Scott et al, 2004;Shiba et al, 2004;Yamakami et al, 2003); for review, see Hurley et al, 2006;Nakayama and Wakatsuki, 2003;Piper and Luzio, 2007. Recently, Puertollano reported that, by using a yeast two-hybrid system, Tom1L1 is able to interact with Tsg101 through a PTAP sequence located near the N-terminus of the GAT domain (see Fig.…”

ENTH domain proteins are cargo adaptors for multiple SNARE proteins at the TGN endosome

“…Adaptor protein complexes (AP) are required to recruit cargo into coated vesicles thus playing an essential role in cargo selectivity of the transport vesicle in traffic between the trans-Golgi network (TGN) and endosomes (Owen et al, 2004). Gga proteins are monomeric clathrin adaptor proteins mediating TGN to the endosome transport (Nakayama and Wakatsuki, 2003). Apart from the AP complexes and the monomeric GGA adaptors, the list is expanding to new sets of adaptors, which are specific to only a particular type of cargo or to one family of cargo (Bonifacino and Rojas, 2006).…”

The Novel Drosophila Lysosomal Enzyme Receptor Protein Mediates Lysosomal Sorting in Mammalian Cells and Binds Mammalian and Drosophila GGA Adaptors

“…They consist of four distinct domains: a VHS domain that binds the acidic dileucine sorting signal (DXXLL) found in the MPRs and other transmembrane cargo proteins; the GAT domain, which interacts with the GTP-bound form of ARF1; a hinge region, which recruits clathrin; and a GAE domain, which exhibits sequence similarity to the ear region of ␥ adaptin and recruits a number of accessory proteins (Ref. 13 and references therein). The interaction with the GGAs leads to the selective incorporation of the MPRs into clathrin-coated vesicles destined for the endosomal/lysosomal sorting route.…”