Structural determinants of lateral gate opening in the protein translocon

ABSTRACT: The heterotrimeric SecY/Sec61 complex is a protein-conducting channel that provides a passage for proteins across the membrane as well as a means to integrate nascent proteins into the membrane. While the first function is common among membrane protein channels and transporters, the latter is unique. Insertion of nascent membrane proteins, one transmembrane segment at a time, by SecY likely occurs through a lateral gate in the channel. Molecular dynamics simulations have been used to investigate the mechanism of gate opening. Opening and closing the gate under different conditions allowed us to identify structural elements that resist opening as well as those that aid closure. SecE, considered to act as a clamp keeping the lateral gate closed, was found to play no such role. Loosening of the plug by lateral gate opening, a potential step in channel gating, was also observed. The simulations revealed that lipids on time scales of up to 1 ís do not flood channels with an open lateral gate. Protein trafficking by the Sec pathway is a cellular process common to all domains of life. Newly formed (or forming), unfolded proteins are targeted by means of an N-terminal signal sequence to the Sec translocon in the endoplasmic reticulum membrane (in eukaryotes) or the cytoplasmi