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Vol. 10, Issue 3, 677-691, March 1999
*Medical Research Council Laboratory for Molecular Cell Biology and
Department of Biochemistry, University College London, London WC1E 6BT,
United Kingdom; and Cluster of differentiation antigen 4 (CD4), the T lymphocyte
antigen receptor component and human immunodeficiency virus
coreceptor, is down-modulated when cells are activated by antigen or
phorbol esters. During down-modulation CD4 dissociates from
p56lck, undergoes endocytosis through clathrin-coated pits, and
is then sorted in early endosomes to late endocytic organelles where it is degraded. Previous studies have suggested that phosphorylation and a
dileucine sequence are required for down-modulation. Using transfected
HeLa cells, in which CD4 endocytosis can be studied in the absence of
p56lck, we show that the dileucine sequence in the cytoplasmic
domain is essential for clathrin-mediated CD4 endocytosis. However,
this sequence is only functional as an endocytosis signal when
neighboring serine residues are phosphorylated. Phosphoserine is
required for rapid endocytosis because CD4 molecules in which the
cytoplasmic domain serine residues are substituted with glutamic acid
residues are not internalized efficiently. Using surface plasmon
resonance, we show that CD4 peptides containing the dileucine sequence
bind weakly to clathrin adaptor protein complexes 2 and 1. The affinity of this interaction is increased 350- to 700-fold when the peptides also contain phosphoserine residues.
Georg-August University, D-37073
Göttingen, Germany
Corresponding author. E-mail address:
m.marsh{at}ucl.ac.uk.
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