9MR4

NAC: Ribosome nascent chain complex(Oxa1L)

This is a non-PDB format compatible entry.

Summary for 9MR4

• Entry DOI: 10.2210/pdb9mr4/pdb
• EMDB information: 48552 71286 71287
• Descriptor: Ubiquitin-ribosomal protein eL40 fusion protein, Large ribosomal subunit protein uL18, uL30, ... (86 entities in total)
• Functional Keywords: nac, mitochondrial sorting, ribosome
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 84
• Total formula weight: 3333978.31

Authors

Maldosevic, E.,Jomaa, A. (deposition date: 2025-01-06, release date: 2025-08-20)

Primary citation

Maldosevic, E.,Gora, R.,Lin, L.L.,Zhou, L.E.,Li, Z.J.,Peskova, Y.,Qi, L.,Shan, S.O.,Jomaa, A.
A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
Biorxiv, 2025

PubMed 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.

PubMed: 40766658
DOI: 10.1101/2025.07.29.667405

Experimental method

ELECTRON MICROSCOPY (2.65 Å)