title: Molecular basis for autoregulatory interaction between GAE domain and hinge region of GGA1.
abstract: Golgi-localizing, gamma-adaptin ear domain homology, ADP ribosylation factor-binding (GGA) proteins and the adaptor protein (AP) complex, AP-1, are involved in membrane traffic between the trans Golgi network and the endosomes. The gamma-adaptin ear (GAE) domain of GGAs and the gamma1 ear domain of AP-1 interact with an acidic phenylalanine motif found in accessory proteins. The GAE domain of GGA1 (GGA1-GAE) interacts with a WNSF-containing peptide derived from its own hinge region, although the peptide sequence deviates from the standard acidic phenylalanine motif. We report here the structure of GGA1-GAE in complex with the GGA1 hinge peptide, which revealed that the two aromatic side chains of the WNSF sequence fit into a hydrophobic groove formed by aliphatic portions of the side chains of conserved arginine and lysine residues of GGA1-GAE, in a similar manner to the interaction between GGA-GAEs and acidic phenylalanine sequences from the accessory proteins. Fluorescence quenching experiments indicate that the GGA1 hinge region binds to GGA1-GAE and competes with accessory proteins for binding. Taken together with the previous observation that gamma1 ear binds to the GGA1 hinge region, the interaction between the hinge region and the GAE domain underlies the autoregulation of GGA function in clathrin-mediated trafficking through competing with the accessory proteins and the AP-1 complex.
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Inoue
authors.forename: Tomoo
authors.initials: T
authors.lastname: Shiba
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ihara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirano
authors.forename: Hironari
authors.initials: H
authors.lastname: Kamikubo
authors.forename: Mikio
authors.initials: M
authors.lastname: Kataoka
authors.forename: Masato
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kato
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakayama
authors.forename: Soichi
authors.initials: S
authors.lastname: Wakatsuki
mesh_terms: D020727:ADP-Ribosylation Factors / Q000502:physiology*; D033982:Adaptor Protein Complex gamma Subunits / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001692:Biological Transport; D002966:Clathrin / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D018808:Transcription Factor AP-1 / Q000737:chemistry*
chemical_list: D033982:Adaptor Protein Complex gamma Subunits; D033942:Adaptor Proteins, Vesicular Transport; D002966:Clathrin; C407306:GGA adaptor proteins; D018808:Transcription Factor AP-1; D020727:ADP-Ribosylation Factors