SND3 is the membrane insertase within a distinct SEC61 translocon complex

Tzu-Jing Yang, Saumyak Mukherjee, Julian D. Langer, Gerhard Hummer and Melanie A. McDowell ()
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Tzu-Jing Yang: Max Planck Institute of Biophysics
Saumyak Mukherjee: Max Planck Institute of Biophysics
Julian D. Langer: Max Planck Institute of Biophysics
Gerhard Hummer: Max Planck Institute of Biophysics
Melanie A. McDowell: Max Planck Institute of Biophysics

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract During the biogenesis of most eukaryotic integral membrane proteins (IMPs), transmembrane domains are inserted into the endoplasmic reticulum membrane by a dedicated insertase or the SEC61 translocon. The SRP-independent (SND) pathway is the least understood route into the membrane, despite catering for a broad range of IMP types. Here, we show that Chaetomium thermophilum SND3 is a membrane insertase with an atypical fold. We further present a cryo-electron microscopy structure of a ribosome-associated SND3 translocon complex involved in co-translational IMP insertion. The structure reveals that the SND3 translocon additionally comprises the complete SEC61 translocon, CCDC47 and TRAPɑ. Here, the SEC61β N-terminus works together with CCDC47 to prevent substrate access to the translocon. Instead, molecular dynamics simulations show that SND3 disrupts the lipid bilayer to promote IMP insertion via its membrane-embedded hydrophilic groove. Structural and sequence comparisons indicate that the SND3 translocon is a distinct multipass translocon in fungi, euglenozoan parasites and other eukaryotic taxa.

Date: 2025
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DOI: 10.1038/s41467-025-65357-z

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