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Structural basis for recognition of acidic-cluster dileucine sequence by GGA1

Nature volume 415, pages 937–941 (2002)Cite this article

Abstract

GGAs (Golgi-localizing, γ-adaptin ear homology domain, ARF-interacting proteins) are critical for the transport of soluble proteins from the trans-Golgi network (TGN) to endosomes/lysosomes by means of interactions with TGN-sorting receptors, ADP-ribosylation factor (ARF), and clathrin1,2. The amino-terminal VHS domains of GGAs form complexes with the cytoplasmic domains of sorting receptors by recognizing acidic-cluster dileucine (ACLL) sequences1,2,3,4,5,6. 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. The VHS domain forms a super helix with eight α-helices, similar to the VHS domains of TOM1 and Hrs. Unidirectional movements of helices α6 and α8, and some of their side chains, create a set of electrostatic and hydrophobic interactions for correct recognition of the ACLL peptide. This recognition mechanism provides the basis for regulation of protein transport from the TGN to endosomes/lysosomes, which is shared by sortilin and low-density lipoprotein receptor-related protein.

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Figure 1: Structure of the GGA1 VHS domain in complex with the ACLL peptide and its sequence comparison with other VHS domains.
Figure 2: Surface representation of the VHS domain interacting with the CI-MPR ACLL peptide.
Figure 3: Peptide binding diagram.

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Acknowledgements

This work was supported in part by Grants-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, from the Japan Society for Promotion of Science (fellowship to H.T.), and from the University of Tsukuba Research Projects.

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Author notes

  1. Tomoo Shiba, Hiroyuki Takatsu and Thomas Earnest: These authors contributed equally to this work

Authors and Affiliations

  1. Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, 305-0801, Ibaraki, Japan

    Tomoo Shiba, Terukazu Nogi, Naohiro Matsugaki, Masato Kawasaki, Noriyuki Igarashi, Mamoru Suzuki, Ryuichi Kato & Soichi Wakatsuki

  2. Foundation for Advancement of International Science (FAIS), Tsukuba, 305-0062, Ibaraki, Japan

    Tomoo Shiba

  3. Institute of Biological Sciences and Gene Research Center, University of Tsukuba, Tsukuba, 305-8572, Ibaraki, Japan

    Hiroyuki Takatsu & Kazuhisa Nakayama

  4. Physical Biosciences Division, Advanced Light Source, Berkeley, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, 94720, California, USA

    Thomas Earnest

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Correspondence to Soichi Wakatsuki.

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Shiba, T., Takatsu, H., Nogi, T. et al. Structural basis for recognition of acidic-cluster dileucine sequence by GGA1. Nature 415, 937–941 (2002). https://doi.org/10.1038/415937a

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