The resting state of the human T-cell receptor

Author:

Notti Ryan Q.ORCID,Yi Fei,Heissel SørenORCID,Molina HenrikORCID,Klebanoff Christopher A.ORCID,Walz ThomasORCID

Abstract

SummaryThe T-cell receptor (TCR) is central to the ligand-dependent activation of T lymphocytes and as such orchestrates both adaptive and pathologic immune processes1. However, major questions remain regarding the structure and function of the human TCR2–4. Here, we present cryogenic electron microscopy structures for the unliganded human TCR in a native-like lipid bilayer, revealing three related conformations that are distinct from previously reported structures of receptors in detergent. These new “closed and compacted” conformations afford insights into the interactions between the TCR and the membrane, including conserved surface patches that make extensive outer leaflet contact, and suggest novel conformational regulation by glycans. We show that the closed/compacted conformations, not the extended one previously reported in detergent5–8, represent the unliganded resting state for the TCRin vivo, underscoring the importance of structural interrogation of membrane proteins in native-like environments. We use conformation-locking disulfide mutants to show that juxtamembrane linker extension is necessary for ligand-dependent TCR activation, demonstrating that TCR-intrinsic conformational change is necessary for TCR activation and opening numerous avenues for immunoreceptor engineering.

Publisher

Cold Spring Harbor Laboratory

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