Abstract
Here, we review recent molecular modelling and simulation studies of the Sec translocon, the primary component/channel of protein translocation into the endoplasmic reticulum (ER) and bacterial periplasm, respectively. Our focus is placed on the eukaryotic Sec61, but we also mention modelling studies on prokaryotic SecY since both systems operate in related ways. Cryo-EM structures are now available for different conformational states of the Sec61 complex, ranging from the idle or closed state over an inhibited state with the inhibitor mycolactone bound near the lateral gate, up to a translocating state with bound substrate peptide in the translocation pore. For all these states, computational studies have addressed the conformational dynamics of the translocon with respect to the pore ring, the plug region, and the lateral gate. Also, molecular simulations are addressing mechanistic issues of insertion into the ER membrane vs. translocation into the ER, how signal-peptides are recognised at all in the translocation pore, and how accessory proteins affect the Sec61 conformation in the co- and post-translational pathways.
Highlights
In eukaryotes, the majority of protein biosynthesis is carried out either by cytosolic ribosomes or by ribosomes that are attached to the endoplasmic reticulum (ER) membrane [1,2]
This study showed that the water molecules in the translocon pore do not behave as in bulk phase since they exhibited anomalous diffusion, had highly retarded rotational dynamics, and aligned their dipoles along the SecY The authors suggested that the water molecules facilitate the interaction between lipids and a peptide located inside the SecY and the dipole alignment of water molecules along the SecY axis may crucially affect the interaction of the positively charged N-terminus of a signal sequence with the translocon and may support membrane integration
The computational studies reviewed here illustrate the important contributions made by molecular dynamics simulations to the aim of better understanding Sec-signal peptide” (SP) dynamics and energetics during translocation
Summary
The majority of protein biosynthesis is carried out either by cytosolic ribosomes or by ribosomes that are attached to the ER membrane [1,2] In the latter case, the newly synthesised “nascent polypeptide chain” (NC) is typically either translocated into the ER or laterally inserted into the ER membrane via an integral membrane protein complex termed translocon (with the exception of tail-anchored membrane proteins). Membrane proteins devoid of a SP are recognised by their first transmembrane (TM) helix In both cases, a lateral gate opens in the translocation pore and either the TM portions of these proteins or the cleaved SP exits laterally into the lipid bilayer. Various human genetic diseases result from single point mutations in the SPs of certain precursor polypeptides [6,7,8]
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