T cell receptors are structures capable of initiating signaling in the absence of large conformational rearrangements

Ricardo Fernandes, David Shore, Mai Vuong, Chao Yu, Xueyong Zhu, Selma Pereira-Lopes, Heather Brouwer, Janet Fennelly, Claire Jessup, Edward Evans, Ian Wilson, Simon Davis

    Research output: Contribution to journalArticlepeer-review

    21 Citations (Scopus)

    Abstract

    Native and non-native ligands of the T cell receptor (TCR), including antibodies, have been proposed to induce signaling in T cells via intra- or intersubunit conformational rearrangements within the extracellular regions of TCR complexes. We have investigated whether any signatures can be found for such postulated structural changes duringTCRtriggering induced by antibodies, using crystallographic and mutagenesis-based approaches. The crystal structure of murine CD3∈ complexed with the mitogenic anti-CD3∈ antibody 2C11 enabled the first direct structural comparisons of antibody-liganded and unliganded forms of CD3∈ from a single species, which revealed that antibody binding does not induce any substantial rearrangements within CD3∈. Saturation mutagenesis of surface-exposed CD3∈ residues, coupled with assays of antibody-induced signaling by the mutated complexes, suggests a new configuration for the complex within which CD3∈ is highly exposed and reveals that no large new CD3∈ interfaces are required to form during antibody-induced signaling. The TCR complex therefore appears to be a structure that is capable of initiating intracellular signaling in T cells without substantial structural rearrangements within or between the component subunits. Our findings raise the possibility that signaling by native ligands might also be initiated in the absence of large structural rearrangements in the receptor.

    Original languageEnglish
    Pages (from-to)13324-13335
    Number of pages12
    JournalJournal of Biological Chemistry
    Volume287
    Issue number16
    DOIs
    Publication statusPublished - 13 Apr 2012

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