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Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors.

ABSTRACT: The alphabeta TCR has recently been suggested to function as an anisotropic mechanosensor during immune surveillance, converting mechanical energy into a biochemical signal upon specific peptide/MHC ligation of the alphabeta clonotype. The heterodimeric CD3epsilongamma and CD3epsilondelta subunits, each composed of two Ig-like ectodomains, form unique side-to-side hydrophobic interfaces involving their paired G-strands, rigid connectors to their respective transmembrane segments. Those dimers are laterally disposed relative to the alphabeta heterodimer within the TCR complex. In this paper, using structure-guided mutational analysis, we investigate the functional consequences of a striking asymmetry in CD3gamma and CD3delta G-strand geometries impacting ectodomain shape. The uniquely kinked conformation of the CD3gamma G-strand is crucial for maximizing Ag-triggered TCR activation and surface TCR assembly/expression, offering a geometry to accommodate juxtaposition of CD3gamma and TCR beta ectodomains and foster quaternary change that cannot be replaced by the isologous CD3delta subunit's extracellular region. TCRbeta and CD3 subunit protein sequence analyses among Gnathostomata species show that the Cbeta FG loop and CD3gamma subunit coevolved, consistent with this notion. Furthermore, restoration of T cell activation and development in CD3gamma(-/-) mouse T lineage cells by interspecies replacement can be rationalized from structural insights on the topology of chimeric mouse/human CD3epsilondelta dimers. Most importantly, our findings imply that CD3gamma and CD3delta evolved from a common precursor gene to optimize peptide/MHC-triggered alphabeta TCR activation.

SUBMITTER: Kim ST

PROVIDER: S-EPMC2936104 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors.

Kim Sun Taek ST Touma Maki M Takeuchi Koh K Sun Zhen-Yu J ZY Dave Vibhuti P VP Kappes Dietmar J DJ Wagner Gerhard G Reinherz Ellis L EL

Journal of immunology (Baltimore, Md. : 1950) 20100726 5

The alphabeta TCR has recently been suggested to function as an anisotropic mechanosensor during immune surveillance, converting mechanical energy into a biochemical signal upon specific peptide/MHC ligation of the alphabeta clonotype. The heterodimeric CD3epsilongamma and CD3epsilondelta subunits, each composed of two Ig-like ectodomains, form unique side-to-side hydrophobic interfaces involving their paired G-strands, rigid connectors to their respective transmembrane segments. Those dimers ar ...[more]

PMID: 20660709

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Project description:Regulatory networks controlling bacterial gene expression often evolve from common origins and share homologous proteins and similar network motifs. However, when functioning in different physiological contexts, these motifs may be re-arranged with different topologies that significantly affect network performance. Here we analyze two related signaling networks in the bacterium Bacillus subtilis in order to assess the consequences of their different topologies, with the aim of formulating design principles applicable to other systems. These two networks control the activities of the general stress response factor sigma(B) and the first sporulation-specific factor sigma(F). Both networks have at their core a "partner-switching" mechanism, in which an anti-sigma factor forms alternate complexes either with the sigma factor, holding it inactive, or with an anti-anti-sigma factor, thereby freeing sigma. However, clear differences in network structure are apparent: the anti-sigma factor for sigma(F) forms a long-lived, "dead-end" complex with its anti-anti-sigma factor and ADP, whereas the genes encoding sigma(B) and its network partners lie in a sigma(B)-controlled operon, resulting in positive and negative feedback loops. We constructed mathematical models of both networks and examined which features were critical for the performance of each design. The sigma(F) model predicts that the self-enhancing formation of the dead-end complex transforms the network into a largely irreversible hysteretic switch; the simulations reported here also demonstrate that hysteresis and slow turn off kinetics are the only two system properties associated with this complex formation. By contrast, the sigma(B) model predicts that the positive and negative feedback loops produce graded, reversible behavior with high regulatory capacity and fast response time. Our models demonstrate how alterations in network design result in different system properties that correlate with regulatory demands. These design principles agree with the known or suspected roles of similar networks in diverse bacteria.

Dataset Information

Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors.

Publications

Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors.

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