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

Saurav Misra, Rosa Puertollano, Yukio Kato, Juan S. Bonifacino and James H. Hurley ()
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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

Nature, 2002, vol. 415, issue 6874, 933-937

Abstract: 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.

Date: 2002
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DOI: 10.1038/415933a

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