Structural conservation and effects of alterations in T cell receptor transmembrane interfaces
Park, S; Krshnan, L; Call, MJ; Call, ME; Im, W
Journal Article in press
T cell receptors (TCRs) are octameric assemblies of type-I membrane proteins in which a receptor heterodimer (alphabeta, deltagamma, or pre-Talphabeta) is associated with three dimeric signaling modules (CD3deltaepsilon, CD3gammaepsilon, and zetazeta) at the T cell or pre-T cell surface. In the human alphabetaTCR, the alpha and beta transmembrane (TM) domains form a specific structure that acts as a hub for assembly with the signaling modules inside the lipid bilayer. Conservation of key polar contacts across the C-terminal half of this TM interface suggests that the structure is a common feature of all TCR types. In this study, using molecular dynamics simulations in explicit lipid bilayers, we show that human deltagamma and pre-Talphabeta TM domains also adopt stable alphabeta-like interfaces, yet each displays unique features that modulate the stability of the interaction and are related to sequences that are conserved within TCR types, but are distinct from the alphabeta sequences. We also performed simulations probing effects of previously reported mutations in the human alphabeta TM interface, and observed that the most disruptive mutations caused substantial departures from the wild-type TM structure and increased dynamics. These simulations show a strong correlation between structural instability, increased conformational variation, and the severity of structural defects in whole-TCR complexes measured in our previous biochemical assays. These results thus support the view that the stability of the core TM structure is a key determinant of TCR structural integrity and suggest that the interface has been evolutionarily optimized for different forms of TCRs.