Alternative titles; symbols
HGNC Approved Gene Symbol: GGA1
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38) : 22:37,608,834-37,633,564 (from NCBI)
Members of the GGA family (see also GGA2, 606005 and GGA3, 606006) are ubiquitous coat proteins that facilitate the trafficking of proteins between the trans-Golgi network and the lysosome.
In database searches for novel proteins related to adaptor protein (AP) components, Hirst et al. (2000) identified sequences that showed significant homology to the C-terminal 'ear' domain of gamma-adaptin (see 603533). The full-length sequences correspond to a family of proteins, the GGAs (Golgi-localized, gamma ear-containing, ARF-binding proteins). (Hirst et al. (2000) noted that the acronym is pronounced 'gigas.') These proteins contain an amino-terminal VHS domain, 1 or 2 coiled-coil domains, and a carboxy-terminal domain homologous to the carboxy-terminal 'ear' domain of gamma-adaptin. However, unlike gamma-adaptin, the GGAs are not associated with clathrin-coated vesicles or with any of the components of the AP-1 complex. GGA1 and GGA2 also are not associated with each other, although they colocalize on perinuclear membranes. Immunogold electron microscopy showed that these membranes correspond to trans elements of the Golgi stack and the trans-Golgi network. The GGA1 gene expresses a 70-kD protein that shares 45% sequence identity with GGA2 and GGA3.
Takatsu et al. (2000) and Dell'Angelica et al. (2000) independently cloned the GGAs.
Suer et al. (2003) reported the crystal structure of the GAT domain of the GGA1 gene. They identified an unanticipated structural similarity to the N-terminal domain of syntaxin-1A (STX1A; 186590). Suer et al. (2003) proposed that the GAT domain is descended from the same ancestor as the syntaxin-1A N-terminal domain, and that both protein families share a common function in binding coiled-coil domain proteins.
Hartz (2017) mapped the GGA1 gene to chromosome 22q13.1 based on an alignment of the GGA1 sequence (GenBank AF190862) with the genomic sequence (GRCh38).
In GST pull-down experiments, Hirst et al. (2000) demonstrated that the GGA carboxy-terminal domains bind to a subset of proteins that bind to the gamma-adaptin carboxy-terminal domain. In yeast, there are 2 GGA genes, each 20% identical to each of the mammalian GGAs. Hirst et al. (2000) demonstrated that deletion of both of these genes causes missorting of the vacuolar enzyme carboxypeptidase Y, resulting in cells with a defective vacuolar morphology phenotype. These results indicated that the GGAs facilitate the trafficking of proteins between the trans-Golgi network and the vacuole, or its mammalian equivalent, the lysosome.
Dell'Angelica et al. (2000) found that treatment with brefeldin A or overexpression of dominant-negative ADP ribosylation factor 1 (ARF1; 103180) caused dissociation of the GGAs from membranes. Dell'Angelica et al. (2000) also disrupted both GGA genes in yeast and found impaired trafficking of carboxypeptidase Y to the vacuole.
Takatsu et al. (2000) demonstrated that the AGEH (adaptor gamma ear homology) domains of the GGA proteins, as well as those of gamma-adaptins, are able to interact with gamma-synergin, which is localized in the trans-Golgi network region and interacts with gamma-adaptin.
The cytosolic tails of both cation-independent (147280) and cation-dependent (154540) mannose 6-phosphate (M6P) receptors contain acidic cluster-dileucine signals that direct sorting from the trans-Golgi network to the endosomal/lysosomal system. Puertollano et al. (2001) found that these signals bind to the VHS domain of the GGAs. The receptors and the GGAs left the trans-Golgi network on the same tubulovesicular carriers. A dominant-negative GGA mutant blocked exit of the receptors from the trans-Golgi network. Thus, Puertollano et al. (2001) concluded that the GGAs appear to mediate sorting of the mannose 6-phosphate receptors at the trans-Golgi network.
Doray et al. (2002) demonstrated that GGA1 and GGA3 and the coat protein adaptor protein-1 (AP-1) complex (see AP1G2, 603534) colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 (see CSNK2A1, 115440) that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. Doray et al. (2002) demonstrated that this autoinhibition could induce the directed transfer of mannose 6-phosphate receptors (154540) from the GGAs to AP-1. Mannose 6-phosphate receptors that were defective in binding to GGAs were poorly incorporated into adaptor protein complex containing clathrin coated vesicles. Thus, Doray et al. (2002) concluded that GGAs and the AP-1 complex interact to package mannose 6-phosphate receptors into AP-1-containing coated vesicles.
Dell'Angelica, E. C., Puertollano, R., Mullins, C., Aguilar, R. C., Vargas, J. D., Hartnell, L. M., Bonifacino, J. S. GGAs: a family of ADP ribosylation factor-binding proteins related to adaptors and associated with the Golgi complex. J. Cell Biol. 149: 81-93, 2000. [PubMed: 10747089] [Full Text: https://doi.org/10.1083/jcb.149.1.81]
Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S. Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. Science 297: 1700-1703, 2002. [PubMed: 12215646] [Full Text: https://doi.org/10.1126/science.1075327]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/23/2017.
Hirst, J., Lui, W. W. Y., Bright, N. A., Totty, N., Seaman, M. N. J., Robinson, M. S. A family of proteins with gamma-adaptin and VHS domains that facilitate trafficking between the trans-Golgi network and the vacuole/lysosome. J. Cell Biol. 149: 67-69, 2000. [PubMed: 10747088] [Full Text: https://doi.org/10.1083/jcb.149.1.67]
Puertollano, R., Aguilar, R. C., Gorshkova, I., Crouch, R. J., Bonifacino, J. S. Sorting of mannose 6-phosphate receptors mediated by the GGAs. Science 292: 1712-1716, 2001. [PubMed: 11387475] [Full Text: https://doi.org/10.1126/science.1060750]
Suer, S., Misra, S., Saidi, L. F., Hurley, J. H. Structure of the GAT domain of human GGA1: a syntaxin amino-terminal domain fold in an endosomal trafficking adaptor. Proc. Nat. Acad. Sci. 100: 4451-4456, 2003. [PubMed: 12668765] [Full Text: https://doi.org/10.1073/pnas.0831133100]
Takatsu, H., Yoshino, K., Nakayama, K. Adaptor gamma-ear homology domain conserved in gamma-adaptin and GGA proteins that interact with gamma-synergin. Biochem. Biophys. Res. Commun. 271: 719-725, 2000. [PubMed: 10814529] [Full Text: https://doi.org/10.1006/bbrc.2000.2700]