Intrinsic dynamics of TARP gamma-2

TARPs (transmembrane AMPA receptor regulatory proteins) are auxiliary subunits of AMPA-type glutamate receptors (AMPARs) that modulate receptor trafficking, gating, and pharmacology. Different TARPs bestow distinct functional properties on AMPARs, influencing synaptic transmission and plasticity. As part of a study on the Structure and organization of AMPA receptor-TARP complexes in the mammalian cerebellum, we determined cryo-EM structures of native AMPARs in complex with TARPs, including GluA1/A4 heteromers with two TARPs, corresponding to the main Bergmann glia AMPAR. To help characterise these receptor complexes, the intrinsic dynamics of TARPs gamma-7 and gamma-2 in POPC membrane bilayer in the absence of the AMPAR was investigated using all-atom molecular dynamics simulations. Our simulations support gamma-7 as the main Bergmann glia TARP as they exhibit a straightening of transmembrane helix 2 (TM2) in 7 simulations, in line with a dominant cryo-EM class. By contrast, the well-studied TARP gamma-2 maintains a pronounced kink in TM2 characteristic of Type I TARPs for 100 ns in 3 simulations. Thus, MD simulations indicate that a straight TM2 is a hallmark of Type II TARPs with the previously uncharacterised gamma-7 having a similar conformation to gamma-5, with different functional properties not consistent with Bergmann glia AMPARs.