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Masato Kawasaki¹, Tomoo Shiba¹, Yoko Shiba², Yoshiki Yamaguchi³, Naohiro Matsugaki¹, Noriyuki Igarashi¹, Mamoru Suzuki^1,, Ryuichi Kato¹, Koichi Kato³, Kazuhisa Nakayama² and Soichi Wakatsuki^1,*

¹ Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan
² Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida-shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan
³ Department of Structural Biology and Biomolecular Engineering, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

GGA (Golgi-localizing, -adaptin ear domain homology, ARF-binding) proteins, which constitute a family of clathrin coat adaptor proteins, have recently been shown to be involved in the ubiquitin-dependent sorting of receptors, through the interaction between the C-terminal three-helix-bundle of the GAT (GGA and Tom1) domain (C-GAT) and ubiquitin. We report here the crystal structure of human GGA3 C-GAT in complex with ubiquitin. A hydrophobic patch on C-GAT helices 1 and 2 forms a binding site for the hydrophobic Ile44 surface of ubiquitin. Two distinct orientations of ubiquitin Arg42 determine the shape and the charge distribution of ubiquitin Ile44 surface, leading to two different binding modes. Biochemical and NMR data strongly suggest another hydrophobic binding site on C-GAT helices 2 and 3, opposite to the first binding site, also binds ubiquitin although weakly. The double-sided ubiquitin binding provides the GAT domain with higher efficiency in recognizing ubiquitinated receptors for lysosomal receptor degradation.

Present address: Institute for Protein Research, Osaka University, 3-2, Yamadaoka, Suita, Osaka 565–0871, Japan.

^* Correspondence: E-mail: soichi.wakatsuki{at}kek.jp

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