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Cloning of ACP33 as a novel intracellular ligand of CD4.

CD4 recruitment to T cell receptor (TCR)-peptide-major histocompatibility class II complexes is required for stabilization of low affinity antigen recognition by T lymphocytes. The cytoplasmic portion of CD4 is thought to amplify TCR-initiated signal transduction via its association with the protein tyrosine kinase p56(lck). Here we describe a novel functional determinant in the cytosolic tail of CD4 that inhibits TCR-induced T cell activation. Deletion of two conserved hydrophobic amino acids from the CD4 carboxyl terminus resulted in a pronounced enhancement of CD4-mediated T cell costimulation. This effect was observed in the presence or absence of p56(lck), implying involvement of alternative cytosolic ligands of CD4. A two-hybrid screen with the intracellular portion of CD4 identified a previously unknown 33-kDa protein, ACP33 (acidic cluster protein 33), as a novel intracellular binding partner of CD4. Since interaction with ACP33 is abolished by deletion of the hydrophobic CD4 C-terminal amino acids mediating repression of T cell activation, we propose that ACP33 modulates the stimulatory activity of CD4. Furthermore, we demonstrate that interaction with CD4 is mediated by the noncatalytic alpha/beta hydrolase fold domain of ACP33. This suggests a previously unrecognized function for alpha/beta hydrolase fold domains as a peptide binding module mediating protein-protein interactions.

Pubmed ID: 11113139


  • Zeitlmann L
  • Sirim P
  • Kremmer E
  • Kolanus W


The Journal of biological chemistry

Publication Data

March 23, 2001

Associated Grants


Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Antigens, CD4
  • COS Cells
  • Carrier Proteins
  • Cell Line
  • Cloning, Molecular
  • Endosomes
  • Golgi Apparatus
  • Humans
  • Ligands
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Protein Binding
  • Sequence Homology, Amino Acid
  • Subcellular Fractions
  • T-Lymphocytes