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

• Recognition of accessory protein motifs by the gamma-adaptin ear domain of GGA3 [6].
• Phosphorylation of GGA3 on S368 causes an increase in the hydrodynamic radius of the protein, indicating a transition to a more asymmetric shape [7].

Anatomical context of GGA3

• Immunofluorescence microscopy showed colocalization of GGAs with Golgi markers, whereas immunoelectron microscopy of GGA3 revealed its presence on coated vesicles and buds in the area of the TGN [8].
• Predominant expression of the short form of GGA3 in human cell lines and tissues [9].
• By double immunofluorescence microscopy, GGA1 and GGA3 were localized with slightly different patterns in both the trans-Golgi network (TGN) and peripheral region [9].
• Mutation of S368 and S372 to a phosphomimic aspartate residue decreases the association of GGA3 with membranes [7].
• These results demonstrate a novel mechanism by which the ubiquitin-ligase Nedd4, via interactions with GGA3 and cargo (LAPTM5), regulates cargo trafficking to the lysosome without requiring cargo ubiquitination [5].

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

• These observations indicate that EGF signaling elicits phosphorylation events that regulate the association of GGA3 with organellar membranes [7].

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

• Using affinity chromatography and nuclear magnetic resonance spectroscopy, we have found that the human GGA3 GAT domain contains two Ub binding motifs that bind to the same surface of ubiquitin [14].

References