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Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains

Author

Listed:
  • Saurav Misra

    (Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • Rosa Puertollano

    (Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health)

  • Yukio Kato

    (Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health)

  • Juan S. Bonifacino

    (Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health)

  • James H. Hurley

    (Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

Abstract

Specific sorting signals direct transmembrane proteins to the compartments of the endosomal–lysosomal system1. Acidic-cluster-dileucine signals present within the cytoplasmic tails of sorting receptors, such as the cation-independent and cation-dependent mannose-6-phosphate receptors, are recognized by the GGA (Golgi-localized, γ-ear-containing, ADP-ribosylation-factor-binding) proteins2,3,4,5. The VHS (Vps27p, Hrs and STAM) domains6 of the GGA proteins are responsible for the highly specific recognition of these acidic-cluster-dileucine signals7,8,9,10. Here we report the structures of the VHS domain of human GGA3 complexed with signals from both mannose-6-phosphate receptors. The signals bind in an extended conformation to helices 6 and 8 of the VHS domain. The structures highlight an Asp residue separated by two residues from a dileucine sequence as critical recognition elements. The side chains of the Asp-X-X-Leu-Leu sequence interact with subsites consisting of one electropositive and two shallow hydrophobic pockets, respectively. The rigid spatial alignment of the three binding subsites leads to high specificity.

Suggested Citation

  • Saurav Misra & Rosa Puertollano & Yukio Kato & Juan S. Bonifacino & James H. Hurley, 2002. "Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains," Nature, Nature, vol. 415(6874), pages 933-937, February.
    • Handle: RePEc:nat:nature:v:415:y:2002:i:6874:d:10.1038_415933a
    DOI: 10.1038/415933a
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