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T Cell Receptor Switches From Closed to Open in Native Membrane, Rewriting Activation Model

Using nanodisc cryo-EM in a membrane-like environment revealed a mechanical opening step with potential to guide safer, more precise T cell therapies.

Overview

  • The Rockefeller University team reports the findings in Nature Communications, presenting a native-like view of the human receptor complex on December 16.
  • In resting conditions the complex appears compact and closed, then extends in a jack-in-the-box motion upon antigen–HLA engagement to initiate signaling.
  • Detergent-based preparations used in prior structural studies likely stripped stabilizing lipids and left the complex artificially open, obscuring the transition.
  • Researchers reconstituted the full eight-protein complex into lipid nanodiscs and imaged it by cryo-EM, a technically demanding approach that preserved key membrane interactions.
  • The structural mechanism suggests ways to tune activation thresholds in engineered receptors and may inform vaccine antigen selection, with further functional validation still required.