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Gene Review

GGA3  -  golgi-associated, gamma adaptin ear...

Homo sapiens

Synonyms: ADP-ribosylation factor-binding protein GGA3, Golgi-localized, gamma ear-containing, ARF-binding protein 3, KIAA0154
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Disease relevance of GGA3

  • We also found that during cerebral ischemia, levels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are increased [1].

High impact information on GGA3

  • Here we report the structures of the VHS domain of human GGA3 complexed with signals from both mannose-6-phosphate receptors [2].
  • RNA interference (RNAi) of GGA3 expression results in accumulation of the cation-independent mannose 6-phosphate receptor and internalized epidermal growth factor (EGF) within enlarged early endosomes [3].
  • PACS-1 links GGA3 to CK2, forming a multimeric complex required for CI-MPR sorting [4].
  • We report a CK2-activated phosphorylation cascade controlling PACS-1- and GGA3-mediated CI-MPR sorting [4].
  • LAPTM5 mutated in its Nedd4-binding sites (PY motifs) or its UIM is retained in the Golgi, as is LAPTM5 expressed in cells in which Nedd4 or GGA3 is knocked-down with RNAi [5].

Biological context of GGA3


Anatomical context of GGA3


Associations of GGA3 with chemical compounds

  • Crystallographic analyses demonstrate that the phosphoserine residue interacts electrostatically with two basic residues on the VHS domain of GGA3, thus providing an additional point of attachment of the acidic-cluster dileucine signal to its recognition module [10].

Physical interactions of GGA3

  • We determined the structure of the GAE domain of human GGA3 in complex with a peptide based on the DFGPLV sequence of the accessory protein Rabaptin-5 and refined it at a resolution of 2.2 A [6].

Regulatory relationships of GGA3


Other interactions of GGA3

  • Using isothermal titration calorimetry, the dissociation constant, K(d), values are 4.0 x 10(-4), 4.1 x 10(-4), and 3.1 x 10(-4) M for VHS domains from GGA1, GGA2, and GGA3, respectively [11].
  • However, none of these cytosolic CLN3 domains was able to interact with AP-1, AP-3, or GGA3 adaptor complexes [12].
  • Reducing GGA3 levels by using short interfering (si)RNA also led to VAMP4 retention in SGs, and inhibition of PC2 activity [13].

Analytical, diagnostic and therapeutic context of GGA3


  1. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. 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. Neuron (2007) [Pubmed]
  2. Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains. Misra, S., Puertollano, R., Kato, Y., Bonifacino, J.S., Hurley, J.H. Nature (2002) [Pubmed]
  3. Interactions of GGA3 with the ubiquitin sorting machinery. Puertollano, R., Bonifacino, J.S. Nat. Cell Biol. (2004) [Pubmed]
  4. A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking. Scott, G.K., Fei, H., Thomas, L., Medigeshi, G.R., Thomas, G. EMBO J. (2006) [Pubmed]
  5. Transport of LAPTM5 to lysosomes requires association with the ubiquitin ligase Nedd4, but not LAPTM5 ubiquitination. Pak, Y., Glowacka, W.K., Bruce, M.C., Pham, N., Rotin, D. J. Cell Biol. (2006) [Pubmed]
  6. Recognition of accessory protein motifs by the gamma-adaptin ear domain of GGA3. Miller, G.J., Mattera, R., Bonifacino, J.S., Hurley, J.H. Nat. Struct. Biol. (2003) [Pubmed]
  7. Epidermal growth factor-dependent phosphorylation of the GGA3 adaptor protein regulates its recruitment to membranes. Kametaka, S., Mattera, R., Bonifacino, J.S. Mol. Cell. Biol. (2005) [Pubmed]
  8. GGAs: a family of ADP ribosylation factor-binding proteins related to adaptors and associated with the Golgi complex. Dell'Angelica, E.C., Puertollano, R., Mullins, C., Aguilar, R.C., Vargas, J.D., Hartnell, L.M., Bonifacino, J.S. J. Cell Biol. (2000) [Pubmed]
  9. Predominant expression of the short form of GGA3 in human cell lines and tissues. Wakasugi, M., Waguri, S., Kametaka, S., Tomiyama, Y., Kanamori, S., Shiba, Y., Nakayama, K., Uchiyama, Y. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  10. Phosphoregulation of sorting signal-VHS domain interactions by a direct electrostatic mechanism. Kato, Y., Misra, S., Puertollano, R., Hurley, J.H., Bonifacino, J.S. Nat. Struct. Biol. (2002) [Pubmed]
  11. Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins. He, X., Zhu, G., Koelsch, G., Rodgers, K.K., Zhang, X.C., Tang, J. Biochemistry (2003) [Pubmed]
  12. A dileucine motif and a cluster of acidic amino acids in the second cytoplasmic domain of the batten disease-related CLN3 protein are required for efficient lysosomal targeting. Storch, S., Pohl, S., Braulke, T. J. Biol. Chem. (2004) [Pubmed]
  13. GGA function is required for maturation of neuroendocrine secretory granules. Kakhlon, O., Sakya, P., Larijani, B., Watson, R., Tooze, S.A. EMBO J. (2006) [Pubmed]
  14. The GAT domains of clathrin-associated GGA proteins have two ubiquitin binding motifs. Bilodeau, P.S., Winistorfer, S.C., Allaman, M.M., Surendhran, K., Kearney, W.R., Robertson, A.D., Piper, R.C. J. Biol. Chem. (2004) [Pubmed]
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