Many proteins must translocate through the protein-conducting Sec61 channel in the eukaryotic endoplasmic reticulum membrane or the SecY channel in the prokaryotic plasma membrane1,2. Proteins with highly hydrophobic signal sequences are first recognized by the signal recognition particle (SRP)3,4 and then moved co-translationally through the Sec61 or SecY channel by the associated translating ribosome. Substrates with less hydrophobic signal sequences bypass the SRP and are moved through the channel post-translationally5,6. In eukaryotic cells, post-translational translocation is mediated by the association of the Sec61 channel with another membrane protein complex, the Sec62–Sec63 complex7,8,9, and substrates are moved through the channel by the luminal BiP ATPase9. How the Sec62–Sec63 complex activates the Sec61 channel for post-translational translocation is not known. Here we report the electron cryo-microscopy structure of the Sec complex from Saccharomyces cerevisiae, consisting of the Sec61 channel and the Sec62, Sec63, Sec71 and Sec72 proteins. Sec63 causes wide opening of the lateral gate of the Sec61 channel, priming it for the passage of low-hydrophobicity signal sequences into the lipid phase, without displacing the channel’s plug domain. Lateral channel opening is triggered by Sec63 interacting both with cytosolic loops in the C-terminal half of Sec61 and transmembrane segments in the N-terminal half of the Sec61 channel. The cytosolic Brl domain of Sec63 blocks ribosome binding to the channel and recruits Sec71 and Sec72, positioning them for the capture of polypeptides associated with cytosolic Hsp7010. Our structure shows how the Sec61 channel is activated for post-translational protein translocation.
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The coordinates of atomic models of the Sec complex without Sec62 were deposited in the Protein Data Bank with accession code 6ND1. The cryo-EM maps of the Sec complex before and after focused refinement with a mask were deposited with accession code EMDB-0440. All other data are available on reasonable request from the corresponding author.
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We thank Z. Yu, R. Huang, and H.-T. Chou at the HHMI Janelia Cryo-EM Facility for help with microscope operation and data collection, E. Twomey for help with data analysis, R. Gilmore for advice and materials, and S. Shao and M. Catipovic for comments on the manuscript. This work was supported by a Jane Coffin Child fellowship to X.W., and an NIGMS award (R01GM052586) to T.A.R. T.A.R. is a Howard Hughes Medical Institute Investigator.
Nature thanks G. von Heijne and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Advances in Health Sciences Education (2019)