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

Specific sorting signals direct transmembrane proteins to the compartments of the endosomal-lysosomal system. 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, gamma-ear-containing, ADP-ribosylation-factor-binding) proteins. The VHS (Vps27p, Hrs and STAM) domains of the GGA proteins are responsible for the highly specific recognition of these acidic-cluster-dileucine signals. 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.

Pubmed ID: 11859375

Authors

  • Misra S
  • Puertollano R
  • Kato Y
  • Bonifacino JS
  • Hurley JH

Journal

Nature

Publication Data

February 21, 2002

Associated Grants

None

Mesh Terms

  • ADP-Ribosylation Factors
  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Cell Line
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli
  • Humans
  • Hydrogen-Ion Concentration
  • Leucine
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptor, IGF Type 2
  • Signal Transduction
  • Structure-Activity Relationship
  • Two-Hybrid System Techniques