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<p>The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to 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 identify 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 increase NAC barrel dynamics and reduce its binding to the ribosome. This impairs the&#xa0;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 mechanistic insights into protein targeting fidelity with broader implications for cellular proteostasis.</p>

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A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月27日

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  • Emir Maldosevic,
  • Radoslaw Jakub Gora,
  • Liangguang Leo Lin,
  • Linyao Elina Zhou,
  • Zexin Jason Li,
  • Yelena Peskova,
  • Ling Qi,
  • Shu-ou Shan,
  • Ahmad Jomaa

摘要

The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to 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 identify 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 increase NAC barrel dynamics and reduce its binding to the ribosome. This impairs the 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 mechanistic insights into protein targeting fidelity with broader implications for cellular proteostasis.