High impact information on GGA1

• Here we report the X-ray structure of the GGA1 VHS domain alone, and in complex with the carboxy-terminal peptide of cation-independent mannose 6-phosphate receptor containing an ACLL sequence [1].
• At the N-terminal end, it forms a parallel coiled-coil homodimer, which binds one GAT domain of GGA1 [2].
• The 2.4-A crystal structure of the GAT domain of human GGA1 reveals a three-helix bundle, with a long N-terminal helical extension that is not conserved in GAT domains that do not bind ARF [3].
• Here we present the structure of the human GGA1 appendage in complex with its cognate binding peptide from the p56 accessory protein (DDDDFGGFEAAETFD) as determined by X-ray crystallography [4].
• The interaction is governed predominantly by packing of the first two phenylalanine residues of the peptide with conserved basic and hydrophobic residues from GGA1 [4].

Biological context of GGA1

• Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy [5].
• Because BACE phosphorylated at serine residues can be identified in human brain, these data suggest that serine phosphorylation of BACE is a physiologically relevant post-translational modification that regulates trafficking in the juxtanuclear compartment by interaction with GGA1 [5].
• Aptamer-binding specifically interferes with the recruitment of CCS, but still permits GGA1 association and casein kinase-dependent phosphorylation, consistent with selective binding site targeting within this short peptide [6].
• Knockdown of GGA1 by RNA interference prevented IRAP from entering, but not exiting, the insulin-responsive compartment [7].
• GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing [8].

Anatomical context of GGA1

• The Golgi-associated, gamma-adaptin-related, ADP-ribosylation-factor binding proteins (GGAs) and adaptor protein (AP)-1 are adaptors involved in clathrin-mediated transport between the trans-Golgi network and endosomal system [4].
• These intermediates are highly pleiomorphic and move toward the peripheral cytoplasm for distances of up to 10 microm with average speeds of approximately 1 microm/s. The labeled clathrin and GGA1 cycle on and off membranes with half-times of 10-20 s, independently of vesicle budding [9].
• Our observations indicate the existence of a novel type of trans-Golgi network-derived carriers containing associated clathrin, GGA1 and adaptor protein-1 that are larger than conventional clathrin-coated vesicles, and that undergo long-range translocation in the cytoplasm before losing their coats [9].
• Cell fractionation showed that the phosphorylated pool of GGA1 resided predominantly in the cytosol and that recruitment onto membranes was associated with dephosphorylation [10].
• The Golgi-associated gamma-adaptin-related ADP-ribosylation factor-binding proteins (GGAs) are critical components of the transport machinery that mediates the trafficking of the mannose 6-phosphate receptors and associated cargo from the trans-Golgi network to the endosomes [11].

Associations of GGA1 with chemical compounds

• A crystal structure of the complex between memapsin 2 phosphoserine peptide and GGA1 VHS was solved at 2.6 A resolution [12].
• Dephosphorylation of GGA1 induced a change in the conformation to an "open" form as measured by gel filtration and sucrose gradient analyses [10].

Physical interactions of GGA1

• Because phosphorylation and GGA1 binding to B1-CT regulate BACE1 transport, these RNA inhibitors could be applied to investigate B1-CT activity without affecting the subcellular localization of BACE1 [6].
• This domain serves as a binding site for at least two proteins, the copper chaperone for superoxide dismutase-1 (CCS), and the Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding (GGA1) protein, and contains a single phosphorylation site [6].

Regulatory relationships of GGA1

• Here, we show that GGA1 regulates the retrograde transport of internalized BACE1 from endosomal compartments to the TGN by direct interaction in a phosphorylation-dependent manner [13].

Other interactions of GGA1

• Gel-immobilized VHS domains of GGA1 and GGA2 also bound to full-length memapsin 2 from cell mammalian lysates [14].
• The interaction of the human GGA1 GAT domain with rabaptin-5 is mediated by residues on its three-helix bundle [15].
• In the present study, we constructed a dominant-negative BIG2 mutant and found that when expressed in cells it induced redistribution of AP-1 and GGA1 and membrane tubulation of the TGN [16].
• By double immunofluorescence microscopy, GGA1 and GGA3 were localized with slightly different patterns in both the trans-Golgi network (TGN) and peripheral region [17].
• GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity [8].

Analytical, diagnostic and therapeutic context of GGA1

• Consistent with confocal fluorescent microscopy, transmission electron microscopy demonstrated the colocalization of GGA1 with adiponectin [18].

References