Alternative titles; symbols
HGNC Approved Gene Symbol: GGA3
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38) : 17:75,236,599-75,262,363 (from NCBI)
For general information on cloning and function of the GGA family, see GGA1 (606004).
By sequencing clones obtained from a size-fractionated immature myeloid cell line cDNA library, Nagase et al. (1995) cloned GGA3, which they designated KIAA0154. The deduced protein shares significant identity with mouse gamma-adaptin (AP1G1; 603533). Northern blot analysis detected GGA3 expression in all tissues and cell lines examined.
Hirst et al. (2000), Takatsu et al. (2000), and Dell'Angelica et al. (2000) independently cloned GGA1, GGA2 (606005), and GGA3. The GGA3 gene encodes a protein of 723 amino acids (Dell'Angelica et al., 2000). GGA3 shares 46% amino acid sequence identity with GGA1 and 38% with GGA2 (Takatsu et al., 2000).
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 (see 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.
BACE (604252) is required for beta-secretase activity and production of the Alzheimer disease (AD; 104300)-associated A-beta protein from APP (104760). Tesco et al. (2007) identified GGA3 as a BACE trafficking molecule and found that it was cleaved by caspase-3 (CASP3; 600636) during apoptosis in a human neuroglioma cell line and in a rat model of cerebral ischemia. As GGA3 was removed by caspase cleavage, BACE was stabilized, leading to elevated beta-secretase cleavage of APP. Silencing of GGA3 by RNA interference led to increased levels of BACE and the APP cleavage products C99 and A-beta. GGA3 protein levels were significantly decreased and were inversely correlated with BACE levels in AD brains, but not in nondemented control brains. Tesco et al. (2007) concluded that depletion of GGA3 is responsible for enhanced BACE levels and beta-secretase activity during ischemia and in AD brain.
By radiation hybrid analysis, Nagase et al. (1995) mapped the GGA3 gene (KIAA0154) to chromosome 17.
Hartz (2017) mapped the GGA3 gene to chromosome 17q25.1 based on an alignment of the GGA3 sequence (GenBank AF190864) with the genomic sequence (GRCh38).
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]
Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. [PubMed: 8590280] [Full Text: https://doi.org/10.1093/dnares/2.4.167]
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]
Tesco, G., Koh, Y. H., Kang, E. L., Cameron, A. N., Das, S., Sena-Esteves, M., Hiltunen, M., Yang, S.-H., Zhong, Z., Shen, Y., Simpkins, J. W., Tanzi, R. E. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54: 721-737, 2007. [PubMed: 17553422] [Full Text: https://doi.org/10.1016/j.neuron.2007.05.012]