Signal peptide mimicry primes Sec61 for client-selective inhibition

Journal article

The protein translocon at the endoplasmic reticulum comprises the Sec61 translocation channel and numerous accessory factors that collectively facilitate the biogenesis of secretory and membrane proteins. Here, we leveraged recent advances in cryo-electron microscopy (cryo-EM) and structure prediction to derive insights into several novel configurations of the ribosome-translocon complex. We show how a transmembrane domain (TMD) in a looped configuration passes through the Sec61 lateral gate during membrane insertion; how a nascent chain can bind and constrain the conformation of ribosomal protein uL22; and how the translocon-associated protein (TRAP) complex can adjust its position during different stages of protein biogenesis. Most unexpectedly, we find that a large proportion of translocon complexes contains RAMP4 intercalated into Sec61’s lateral gate, widening Sec61’s central pore and contributing to its hydrophilic interior. These structures lead to mechanistic hypotheses for translocon function and highlight a remarkably plastic machinery whose conformations and composition adjust dynamically to its diverse range of substrates

Authors: Rehan, S; Tranter, D; Sharp, PP; Craven, GB; Lowe, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Chemical Biology
• Volume: 19
• Issue: 9
• Pages: 1054-1062
• Publication date: 2023-05-11
• DOI: 10.1038/s41589-023-01326-1
• EISSN: 1552-4469
• ISSN: 1552-4450
• Language: English
• Keywords: Biology; Chemistry; Genetics; Gene; Peptide sequence; Antibody; Molecular mimicry; Zoology; Mimicry; Peptide; Biophysics; Biochemistry; Signal peptide; Cell biology