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.
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
Nature
Date: Feb. 21, 2002
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