Mechanisms Contributing to T Cell Receptor Signaling and Assembly Revealed by the Solution Structure of an Ectodomain Fragment of the CD3ϵγ Heterodimer

نویسندگان

  • Zhen-Yu J. Sun
  • Ki Seok Kim
  • Gerhard Wagner
  • Ellis L. Reinherz
چکیده

complexity of MHC bound peptides and the ability of subtle variation in peptide ligands to dramatically affect the outcome of T cell activation and differentiation (Alam et al.Summary tains one extracellular immunoglobulin (Ig)-like domain, a membrane-proximal stalk region, a transmembrane The T cell receptor (TCR) consists of genetically di-helix, and a cytoplasmic domain. The interaction be-verse disulfide-linked ␣ and ␤ chains in noncovalent tween a TCR ␣␤ chain heterodimer and a pMHC initiates association with the invariant CD3 subunits. CD3⑀ and a cascade of downstream signaling events via the immu-CD3␥ are integral components of both the TCR and noreceptor tyrosine-based activation motifs (ITAM) in pre-TCR. Here, we present the solution structure of a The various side-to-side hydrophobic interface between the two CD3 chains exhibit different interactions with intracellu-C2-set immunoglobulin-like domains and parallel pair-lar signaling factors, thus inducing distinct patterns of ing of their respective C-terminal ␤ strands are re-cellular protein tyrosine phosphorylation upon activa-vealed. Mutational analysis confirms the importance These post-association. These biochemical and structural analy-translational modifications provide necessary informa-ses offer insights into the modular pairwise association to the cell about qualitative and quantitative aspects tion of CD3 invariant chains. More importantly, the of TCR ligation. Since the TCR ␣␤ chains do not possess findings suggest how the rigidified CD3 elements par-functionally relevant cytoplasmic domains, it is the CD3 ticipate in TCR-based signal transduction. components which mediate critical " data transfer " from the external environment to the intracellular com-Introduction partment. The CD3 subunits are also required for cell surface The TCR is essential for immune recognition by a T expression of the TCR heterodimers on mature T lym-lymphocyte of a specific antigenic peptide bound to phocytes. In the absence of CD3⑀ or CD3␨ chain expres-a major histocompatibility complex molecule (pMHC) sion due to genetic mutations or following anti-CD3⑀ Rein-is a severely reduced number of TCR molecules on the herz et al., 1983). Binding of the Fab-like clonotypic ␣␤ cell surface as shown by in vitro analysis (Hall et al., heterodimer to pMHC alters the adjacent CD3 compo-been disrupted by homologous recombination, there However, due to lack of CD3 structures, essentially no is a developmental blockade of thymocytes at the atomic detail is currently available about the initial CD4 Ϫ CD8 Ϫ double negative (DN) stage (Haks et al., events in the TCR signaling process.

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عنوان ژورنال:
  • Cell

دوره 105  شماره 

صفحات  -

تاریخ انتشار 2001