CD4 is a co-receptor in the cellular immune response. It increases the avidity
of association between a T cell and an antigen-presenting cell by interacting
with non-polymorphic portions of the complex between class II major
histocompatibility complex (MHC) and T-cell receptor (TCR) molecules, and it
contributes directly to signal transduction through its cytoplasmic association
with the lymphocyte kinase Lck. CD4 also serves as the high-affinity receptor
for cellular attachment and entry of the human immunodeficiency virus (HIV). The
extracellular portion of CD4 comprises four immunoglobulin-like domains (D1-D4).
This part of human CD4 (residues 1-369) has been characterized as a recombinant
soluble protein (sCD4), and crystal structures have been described for the human
D1D2 fragment and for the rat D3D4 fragment. We have now determined the
structures of intact sCD4 in three crystal lattices. These structures have a
hinge-like variability at the D1D2 to D3D4 junction that might be important in
immune recognition and HIV fusion, and a common dimeric association through D4
domains. Dynamic light scattering measurements and chemical crosslinking of sCD4
corroborate dimerization at high protein concentration. We suggest that such
dimers mayhave relevance as mediators of signal transduction in T cells.
