Sec61 translocon complex (Sec61)

The Sec61 translocon complex is a highly conserved heterotrimeric membrane protein assembly located in the endoplasmic reticulum (ER) of eukaryotic cells (UniProt Consortium, 2023). It serves as the central channel through which nearly all secreted and integral membrane proteins must pass to enter the secretory pathway. The complex consists of the pore-forming Sec61α subunit along with the smaller Sec61β and Sec61γ subunits, which together coordinate with the ribosome to facilitate co-translational translocation (Voorhees & Hegde, 2016, Science). Beyond its fundamental role in proteostasis, the Sec61 complex is a critical node in various pathologies; for instance, it is exploited by certain viruses for glycoprotein synthesis and is often overexpressed in aggressive cancers to support rapid growth. Pharmacological targeting of Sec61 with small molecules like Apratoxin A, Mycolactone, and Ipomoeassin F has demonstrated potent anti-proliferative and anti-inflammatory effects by inducing ER stress and blocking the production of essential growth factors and cytokines (Hall et al., 2014, PLOS Pathogens; Zhang et al., 2021, Journal of Medicinal Chemistry). However, because of its essential role in global protein secretion, developing inhibitors with sufficient therapeutic windows remains a significant challenge, often leading to concerns regarding systemic toxicity and immunosuppression. Recent advances in substrate-selective inhibitors offer a potential path forward for more precise therapeutic interventions (Klein et al., 2021, Nature Communications).

Other names

Sec61 complexProtein translocation channelER transloconSec61p complexSec61 alpha/beta/gamma complex

Inhibition of the Sec61-mediated protein translocation across the endoplasmic reticulum membrane by either sterically blocking the channel pore or interfering with the recognition of the signal peptide or transmembrane domain of nascent polypeptides (Paatero et al., 2016, Nature Communications; Gérard et al., 2020, PubMed).