Structural variability and concerted motions of the T cell receptor – CD3 complex

Abstract

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C_ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights on conformational changes of the complex in response to tilt-inducing forces on antigen-bound TCRs.

TCR-pMHC complex formation triggers CD3 dynamics

“…In the TCR-CD3 system, the TCR EC folded over the CD3 proteins, and the TCR adopted predominantly bent conformations (smaller tilt angles) with a peak in the angular distribution of approximately 104° (Figure 4B). Such TCR bending has been observed in previous TCR-CD3 simulations 17 . In contrast, in the TCR-CD3-pMHC system, the TCRs had more extended and open conformations (larger tilt angles) with a peak in the angular distribution of approximately 150°, which was close to the initial angle observed in the cryo-EM structures.…”

“…The study by Dong and co-workers 15 , for example, employed 0.1% glutaraldehyde for cross linking transmembrane helices while that of Sušac and co-workers used graphene coated grids and Fabs for TCR stabilization 18 . The absence of a native membrane is especially relevant since movement of the TCR-EC was found to be coupled to changes in the transmembrane helices in the previous work by Pandey and co-workers 17 . Furthermore, in TCR-CD3 MD simulations reported to date, TCR bending was observed consistently, despite the use of three different forcefields – Amber99SB-ILDN 17 , and CHARMM36m and the Martini 3 forcefields, in this work.…”

“…This suggested that the TCR tilt is not sufficient to describe the interactions between TCR and CD3. In the simulations of Pandey et al 17 , the TCR EC not only varied its tilt, but also rotated. Indeed, calculation of the TCR EC rotation showed that the proline mutant had a skewed TCR EC – the PP mutant adopted rotation angles as low as ∼75°; in contrast, rotation angles lower than 100° were almost absent in the wild-type TCR (Figure S6E-F).…”

“…Interestingly, the extracellular domain (EC) of the TCR was bent with respect to the membrane. Subsequent molecular dynamics simulations of the TCR showed that the angle between the TCR EC and transmembrane domain (TM) is dynamic, allowing the TCR EC to adopt a range of different conformations 16, 17 . In 2022, the structure of a pMHC-bound TCR-CD3 complex revealed that the TCR was unchanged by the binding to a soluble pMHC 18 .…”

The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States

“…Thus, concerning this region, such correlations are weak in the unbound state; they increase in the ESO9C model and disappear in the 1G4:ESO4D. A significative correlation between the C β region and CD3 ε and CD3 γ chains were also observed in a very recent work on the unbound TCR:CD3 complex [ 49 ].…”