Protein transport protein Sec61 subunit alpha isoform 1 (SEC61A1) (SEC61A1)

Protein transport protein Sec61 subunit alpha isoform 1 (Sec61α1) is the central, pore-forming component of the Sec61 translocon complex, a universally conserved heterotrimeric assembly located in the endoplasmic reticulum (ER) membrane. It serves as the primary gateway for the entry of nearly all secretory and most membrane proteins into the ER, facilitating both co-translational and post-translational translocation. Beyond its role in protein transport, Sec61α1 functions as a passive calcium leak channel, contributing to cellular calcium homeostasis and signaling. Mutations in the SEC61A1 gene are associated with various pathologies, including autosomal dominant tubulointerstitial kidney disease and severe congenital neutropenia, while its upregulation is linked to several cancers. Pharmacological targeting of Sec61α1 with small-molecule inhibitors like KZR-261 and mycolactone offers a novel therapeutic strategy by blocking the biogenesis of specific oncogenic or inflammatory proteins, thereby inducing ER stress and apoptosis in target cells. However, the essential nature of the translocon in cellular proteostasis presents significant challenges in achieving therapeutic selectivity and managing potential systemic toxicity.

Other names

SEC61A1SEC61AHSEC61SEC61Sec61 alpha-1ADTKD5CVID15HNFJ4SEC61 translocon alpha 1 subunit

Inhibition of protein translocation into the endoplasmic reticulum by binding to the Sec61 channel and stabilizing the plug domain in a closed state, thereby preventing substrate polypeptide insertion.