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DxxxLL Motif: A Binding
Site for Adaptor Protein-1 and Adaptor Protein-2 in Vitro
Institute of Medical Microbiology and Immunology, University of Copenhagen, The Panum Institute, DK-2200
Copenhagen, Denmark
Several receptors are downregulated by internalization after ligand binding. Regulation of T cell
receptor (TCR) expression is an important step in T
cell activation, desensitization, and tolerance induction.
One way T cells regulate TCR expression is by phosphorylation/dephosphorylation of the TCR subunit
clusters of differentiation (CD)3
. Thus, phosphorylation of CD3 serine 126 (S126) causes a downregulation of the TCR. In this study, we have analyzed the
CD3 internalization motif in three different systems in
parallel: in the context of the complete multimeric TCR; in monomeric CD4/CD3 chimeras; and in vitro
by binding CD3 peptides to clathrin-coated vesicle
adaptor proteins (APs). We find that the CD3
D127xxxLL131/132 sequence represents one united motif
for binding of both AP-1 and AP-2, and that this motif
functions as an active sorting motif in monomeric CD4/
CD3 molecules independently of S126. An acidic amino acid is required at position 127 and a leucine (L)
is required at position 131, whereas the requirements
for position 132 are more relaxed. The spacing between
aspartic acid 127 (D127) and L131 is crucial for the
function of the motif in vivo and for AP binding in
vitro. Furthermore, we provide evidence indicating that
phosphorylation of CD3 S126 in the context of the
complete TCR induces a conformational change that
exposes the DxxxLL sequence for AP binding. Exposure of the DxxxLL motif causes an increase in the
TCR internalization rate and we demonstrate that this
leads to an impairment of TCR signaling. On the basis
of the present results, we propose the existence of at
least three different types of L-based receptor sorting
motifs.
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