Cloning of ACP33 as a Novel Intracellular Ligand of CD4

• Published in: The Journal of biological chemistry 2001-03, Vol.276 (12), p.9123-9132
• Main Authors: Zeitlmann, Lutz, Sirim, Pinar, Kremmer, Elisabeth, Kolanus, Waldemar
• Format: Article
• Language: English
• Subjects: ACP33 protein; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; CD4 antigen; CD4 Antigens - metabolism; Cell Line; Cloning, Molecular; COS Cells; Endosomes - metabolism; Golgi Apparatus - metabolism; Humans; Ligands; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; Molecular Sequence Data; Mutation; Phenotype; Protein Binding; Sequence Homology, Amino Acid; Subcellular Fractions - metabolism; T-Lymphocytes - immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M009270200

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 p56lck. 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 p56lck, 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 clusterprotein 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 α/β hydrolase fold domain of ACP33. This suggests a previously unrecognized function for α/β hydrolase fold domains as a peptide binding module mediating protein-protein interactions.