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bioRxiv · 10.1101/2023.08.22.554360

The resting state of the human T-cell receptor

Notti, R. Q.·Yi, F.·Heissel, S.·Molina, H.·Klebanoff, C. A.·Walz, T.
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Abstract

The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain(1-4). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR-CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the "open and extended" conformation seen in detergent(5-8), the unliganded TCR-CD3 in nanodiscs adopts two related "closed and compacted" conformations that represent its physiologic resting state in vivo. By contrast, the HLA-bound complex adopts the open and extended conformation, and conformation-locking disulfide mutants show that ectodomain opening is necessary for maximal ligand-dependent T-cell activation. Together, these results reveal allosteric conformational change during TCR activation and highlight the importance of native-like lipid environments for membrane protein structure determination.

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Notti, R. Q., Yi, F., Heissel, S., Molina, H., Klebanoff, C. A., Walz, T.. 2023-08-22. The resting state of the human T-cell receptor. https://doi.org/10.1101/2023.08.22.554360

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