Figure 8. Model for cotransin-mediated inhibition of TMD integration.
Following RNC targeting to Sec61 (left panel), the TMD docks to a notch in the cytosolic tip of the lateral gate created by the separation of TM2b from TM8 (middle panel). This otherwise transient, pre-integrated configuration is stabilized by CT8 binding to the lumenal plug region of Sec61α. Interactions between the TMD and the lateral gate facilitate gate opening and TMD movement to a second site on the lipid-exposed face of the lateral gate (right panel). CT8 blocks TMD movement from the cytosolic docking site to the external, lipid-exposed site. Structural models (bottom) were adapted from PDB entries 1RH5 (left panel, closed lateral gate), 2ZJS (middle panel, pre-integrated configuration), and 3J00/3J01 (right panel, integrated configuration). The model for the pre-integrated TMD configuration was approximated by manually placing the TMD (modeled as an α-helix) into the cytosolic vestibule between TM2b and TM7 (PDB entry: 2ZJS), consistent with the BMOE crosslinking data. Lateral gate helices TM2b/3 and TM7/8 are blue and green, respectively, while the TMD helix is red.