Journal Article

The resting and ligand-bound states of the membrane-embedded human T-cell receptor-CD3 complex

Yi, Fei, Molina, Henrik, Heissel, Søren, Klebanoff, Christopher A, Bush, Martin W, Das, Pujita, Notti, Ryan Q, Molvi, Zaki, Walz, Thomas

2024

Overview

The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain( ). 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( ), the unliganded TCR-CD3 in nanodiscs adopts two related \"closed and compacted\" conformations that represent its physiologic resting state . 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.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Biochemistry