Molecular interactions between extracellular components of the T‐cell receptor signaling complex

Summary: The structural and biochemical basis of antigen recognition by the T‐cell receptor (TCR)‐CD3 signaling complex has been illuminated greatly over the past few years. Structural biology has contributed enormously to this understanding through the determination of crystal structures of many of the individual components of this complex, and some of the complexes, A number of general principles can be derived for the structure of the aP TCR and its interaction with peptide–major histocompatibility complex (pMHC) in class 1 systems, as well as interaction of the CDS co‐receptor with MHC, Large buried surface areas within the protein–protein interfaces, and varying degrees of shape complementarity appear critical for modulating the stability of the multicomponent, low‐affinity macromolecular complexes consisting of TCR, pMHC, CDS or CD4, and CD3 γ, δ, ɛ and ζ, Significant structural alterations in TCR and pMHC, upon complex formation, hint at an as yet unclear role for conformational change in both recognition and activation. Subtle chemical alterations in key peptide residues which contact the TCR can have dramatic agonist or antagonist effects on receptor activation, which correlate only loosely with the TCR/pMHC complex affinity, implying an ability of the signaling complex to “sense” for differences in the interface. The stoichiometry of an activated TCR signaling complex is stain an unresolved issue, as is the structure and disposition of the CD3 components. However, functional experiments are bridging this gap and providing us with preliminary working models of the multimeric assemblies.

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