Phosphoregulation of sorting signal-VHS domain interactions by a direct electrostatic mechanism

Nat Struct Biol. 2002 Jul;9(7):532-6. doi: 10.1038/nsb807.


Phosphorylation of the cytosolic tails of transmembrane receptors can regulate their intracellular trafficking. The structural basis for such regulation, however, has not been explained in most cases. The cytosolic tail of the cation-independent mannose 6-phosphate receptor contains a serine residue within an acidic-cluster dileucine signal that is important for the function of the receptor in the biosynthetic sorting of lysosomal hydrolases. We show here that phosphorylation of this Ser enhances interactions of the signal with its recognition module, the VHS domain of the GGA proteins. Crystallographic analyses demonstrate that the phosphoserine residue interacts electrostatically with two basic residues on the VHS domain of GGA3, thus providing an additional point of attachment of the acidic-cluster dileucine signal to its recognition module.

MeSH terms

  • ADP-Ribosylation Factors / chemistry*
  • ADP-Ribosylation Factors / metabolism*
  • Adaptor Proteins, Vesicular Transport*
  • Amino Acid Sequence
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphoserine / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Receptor, IGF Type 2 / chemistry*
  • Receptor, IGF Type 2 / genetics
  • Receptor, IGF Type 2 / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Static Electricity
  • Two-Hybrid System Techniques


  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • GGA adaptor proteins
  • Receptor, IGF Type 2
  • Recombinant Fusion Proteins
  • Phosphoserine
  • ADP-Ribosylation Factors

Associated data

  • PDB/1LF8