Dimeric association and segmental variability in the structure of human CD4

Area of Science:

• Structural biology
• Immunology
• Virology

Background:

• CD4 is a crucial co-receptor in cellular immunity, facilitating T cell interactions and signal transduction via Lck.
• CD4 also functions as the primary receptor for Human Immunodeficiency Virus (HIV) entry into cells.
• Previous structural studies characterized fragments of CD4, but the intact soluble form (sCD4) remained less understood.

Purpose of the Study:

• To determine the three-dimensional structure of intact soluble CD4 (sCD4).
• To investigate potential structural flexibility and oligomeric states of sCD4 relevant to its biological functions.

Main Methods:

• X-ray crystallography was employed to obtain high-resolution structures of sCD4 in three different crystal lattices.
• Dynamic light scattering and chemical crosslinking experiments were performed to assess sCD4's oligomeric state in solution.

Main Results:

• The crystal structures revealed a hinge-like flexibility between the D1D2 and D3D4 domains of sCD4.
• A consistent dimeric association of sCD4 through its D4 domains was observed in the crystal structures.
• Solution-based experiments corroborated the dimerization of sCD4 at higher protein concentrations.

Conclusions:

• The structural flexibility and observed dimerization of sCD4 may be critical for its roles in immune recognition and HIV fusion.
• sCD4 dimerization could be a mechanism for mediating signal transduction in T cells.