T cell receptors are structures capable of initiating signaling in the absence of large conformational rearrangements
| Autor: | Mai T. Vuong, Chao Yu, David A. Shore, Heather Brouwer, Xueyong Zhu, Claire M. Jessup, Simon J. Davis, Ricardo A. Fernandes, Ian A. Wilson, Edward J. Evans, Selma Pereira-Lopes, J A Fennelly |
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| Rok vydání: | 2012 |
| Předmět: |
Protein Structure
CD3 Complex Protein Conformation Immunology Receptors Antigen T-Cell Epitopes T-Lymphocyte Biology Crystallography X-Ray Biochemistry Jurkat cells Epitope 03 medical and health sciences Immunoglobulin Fab Fragments Jurkat Cells Mice Structure-Activity Relationship 0302 clinical medicine Protein structure Animals Humans Site-directed Mutagenesis Receptor Site-directed mutagenesis Molecular Biology 030304 developmental biology 0303 health sciences Crystallography T-cell receptor Antibodies Monoclonal Cell Biology 3. Good health Cell biology Protein Structure Tertiary Receptor Triggering Mutagenesis Site-Directed Signal transduction Dimerization T cell Receptor 030217 neurology & neurosurgery Intracellular Signal Transduction |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Background: The T cell receptor (TCR) triggers signaling in T cells via an unknown mechanism. Results: The structure of the signaling subunit, CD3ϵ, is unchanged by signal-inducing antibodies, and mutations that would block intersubunit rearrangements do not affect signaling. Conclusion: Antibodies trigger TCR signaling without inducing large structural rearrangements. Significance: TCR triggering might generally occur in the absence of large structural rearrangements. 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 during TCR triggering induced by antibodies, using crystallographic and mutagenesis-based approaches. The crystal structure of murine CD3ϵ complexed with the mitogenic anti-CD3ϵ antibody 2C11 enabled the first direct structural comparisons of antibody-liganded and unliganded forms of CD3ϵ from a single species, which revealed that antibody binding does not induce any substantial rearrangements within CD3ϵ. Saturation mutagenesis of surface-exposed CD3ϵ residues, coupled with assays of antibody-induced signaling by the mutated complexes, suggests a new configuration for the complex within which CD3ϵ is highly exposed and reveals that no large new CD3ϵ 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. |
| Databáze: | OpenAIRE |
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