Secreted and integral membrane proteins compose up to one-third of the
biological proteome. These proteins contain hydrophobic signals that direct
their translocation across or insertion into the lipid bilayer by the Sec61
protein-conducting channel. The molecular basis of how hydrophobic signals
within a nascent polypeptide trigger channel opening is not understood. Here, we
used cryo-electron microscopy to determine the structure of an active Sec61
channel that has been opened by a signal sequence. The signal supplants helix 2
of Sec61α, which triggers a rotation that opens the central pore both axially
across the membrane and laterally toward the lipid bilayer. Comparisons with
structures of Sec61 in other states suggest a pathway for how hydrophobic
signals engage the channel to gain access to the lipid bilayer.
