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Visualizing Antigen Specific CD4+ T Cells using MHC Class II Tetramers
Published on: March 6, 2009
Dimeric association and segmental variability in the structure of human CD4
H Wu1, P D Kwong, W A Hendrickson
1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Insights
Researchers determined the structure of soluble CD4 (sCD4), revealing a flexible hinge and dimerization. This dimerization may play a role in T cell signaling and immune recognition.
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.
Abstract:
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.
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