Year: 2026
Type: article
Abstract: The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to the signal recognition particle (SRP) to ensure the fidelity of protein targeting to the endoplasmic reticulum (ER). However, the mechanism by which NAC prevents the mistargeting of nascent mitochondrial proteins remains unclear. Here, we identified a molecular switch in NAC that allows its central barrel domain to adopt a stabilized conformation on ribosomes exposing a mitochondrial targeting sequence (MTS). Mutations of the MTS on the nascent chain or in the NAC switch region increases NAC barrel dynamics and reduces its binding to the ribosome. This leads to an impaired ability of NAC to prevent mistargeting by SRP and causes ER stress in human cells. Our work reveals how NAC detects nascent mitochondrial proteins early in translation and prevents their promiscuous access to SRP, elucidating the structural basis that underlies this role and providing novel insights into protein targeting fidelity with broader implications for cellular proteostasis.
Source: Nature Communications
Institutions: University of Virginia, California Institute of Technology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1168517235, G3740809466, Molecular Electron Microscopy Core Facility Improvements, Targeted Infusion Grant: Development of a Virtual and Augmented Reality Laboratory for Research and Education at Tennessee State University, Regulation of mitochondrial dynamics by ERAD, G5309090845, G5369305972, G5996226504, Fidelity and Regulation of Signal Recognition Particle, G9000003349, G9000150961, G9000184831, Training in Cell and Molecular Biology, Unraveling the Mechanisms of Protein Sorting and Localization to Organelles
OpenAlex ID: W7141755430